digestions and detoxification by

Digestions and Detoxification

ByStephen Eddey M.H.Sc.,B.H.Sc.,Dip.App.Sc.,Ass.Dip.App.Sc.,Cert.I.V.

(Workplace and Training).PrincipalHealth Schools Australia

Digestion - Stomach

Acid is the key to optimal stomach digestion. Arginine boost blood flow to the stomach and increases stomach acid.

Brzozowski, T., et al. Role of L-arginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing. Journal of Gastroenterology. 32(4):442-452, 1997.

Glutamine Boosts Stomach acids

These results show that a Gln-enriched enteral diet increased splanchnic blood flow, which was not mediated by pancreatic glucagon or increased nitric oxide production as determined by urinary nitrate excretion.

Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic blood flow in the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.

Ginger Protects the Stomach

“The results of this study demonstrate that the extract in the dose of 500 mg/kg orally exert highly significant cytoprotection against 80% ethanol, 0.6M HC1, 0.2M NaOH and 25% NaCl induced gastric lesions. The extract also prevented the occurrence of gastric ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs) and hypothermic restraint stress. These observations suggest cytoprotective and anti-ulcerogenic effect of the ginger.”

Al-Yahya, M. A., et al. Gastro protective activity of ginger in albino rats. Am J Chinese Med. 17(1-2):51-56, 1989.

Glutamine Increases Blood Flow to the

Pancreas“In the glutamine-enriched group, higher organ

blood flows were measured in the stomach (51%), the pancreas (35%), small intestine (32%), and colon (55%), compared with controls. No differences were found in systemic hemodynamic parameters between the control and Gln-supplemented groups.

Houdijk, A. P., et al. Glutamine-enriched enteral diet increases splanchnic blood flow in the rat. Am J Physiol. 267(6 Part 1):G1035-G1040, 1994.

The Liver: Why is it so big?

BiotransformationBiotransformation is the metabolic

alteration of toxins and other chmicals by phase 1 (cytochrome P450) and phase 2 (conjugating) enzymes.

These enzymes are involved in both the synthesis of steroid hormones, and the clearance (detoxification) of harmful endogenous and exogenous compounds.

Biotransformational activation of substrates

“Human beings are faced with a continuous burden of reactive chemical entities that are formed during biotransformation of foreign compounds, as well as from endogenous molecules.”

Rinaldi R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metab Disp. 2002;30:1053-1058.

Biotransformational activation of substrates

“Many developmental toxicants and teratogens require prior metabolism to reactive species or free radicals to exert toxicity. Thus the knowledge of conceptal biotransformation is absolutely critical in understanding toxicity of these chemicals”

Kulkarni AP. Role of biotransformation in conceptal toxicity of drugs and other chemicals. Curr Pharm Des. 2001 Jun;7(9):833-57.

BIOTRANSFORMATION IS A PROTECTIVE MECHANISM

“Along with strategies such as sequestration, scavenging and binding, catalytic biotransformation evolved as an important biochemical protection mechanism against toxic chemical species.”

Sheehan D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J 2001;360:1-16

ENZYMES MEDIATE BIOTRANSFORMATION

“Cells possess an impressive array of enzymes capable of biotransforming a wide range of different chemical structures and functionalities.”

Sheehan, D. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem. J. 2001; 360: 1-16

BIOTRANSFORMATION IS IMPERATIVE FOR

SURVIVALThe perpetuation of human and other

animal species depends, among other factors, on successful defence against the deleterious effects of naturally occurring toxic chemicals in plants and synthetic toxicants.”

Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825

UNDERSTANDING BIOTRANSFORMATION

IMPROVES DRUG THERAPY

“biotransformation represents a key element in understanding the pharmacological efficacy of drugs and the toxicity (of) pesticides, industrial/ environmental chemicals, and naturally occurring toxicants”

Kulkarni K. Lipoxygenase - a versatile biocatalyst for biotransformation of endobiotics and zenobiotics. Cell.Mol. Life Sci. 2001; 58:1805-1825

THE PHASES OF DETOXIFICATION

The enzymic detoxification of xenobiotics has been classified into two distinct phases which act in a tightly integrated manner.


Phase I & II detoxification

THE ROLE OF PHASE I

“Phase I is catalysed mainly by the cytochrome P450 system. This family of microsomal proteins is responsible for a range of reactions, of which oxidation appears to be the most important”


THE ROLE OF PHASE II

“Phase II enzymes catalyse the conjugation of activated xenobiotics to an endogenous water-soluble substrate, such as reduced glutathione (GSH), UDP-glucuronic acid or glycine”


Phytonutrients regulate biotransformation

“Induction or inhibition of biotransformational enzymes, enzymes that activate or detoxify numerous xenobiotics, is one mechanism by which vegetables may alter cancer risk.”

Lampe J. et al. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000; 21(6):1157-62

BIOTRANSFORMATIONAL ENZYMES

“Biotransformation enzymes, such as the cytochrome P450 (CYP) isoenzymes, are essential for initiating conversion of lipophilic xenobiotics into more hydrophilic, water-soluble metabolites.”


Functions of Cytochrome P450 Enzymes

• The synthesis and degradation of endogenous steroid hormones, vitamins and fatty acid derivatives

• Metabolism of drugs, environmental pollutants and carcinogens.

Honkakoski P. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J 2000;347:321-337

THE IMPORTANCE OF BIOTRANSFORMATION

“They (CYP) reduce the half-life of and duration of exposure to xenobiotics and prevent accumulation of the parent compounds.”


Phase 1 Detoxification

Biotransformational enzymes

“Cytochrome p450’s support the oxidative, peroxidative and reductive metabolism of such endogenous and xenobiotic substrates as environmental pollutants, agrochemicals, plant allelochemicals, steroids, prostaglandins and fatty acids.”

Danielson PB. The cytochrome P450 superfamily: biochemistry, evolution and drug metabolism in humans. Curr Drug Metab. 2002 Dec;3(6):561-

97

Biotransformational enzymes

“They also display complex sex-, tissue- and development-specific expression patterns which are controlled by hormones or growth factors, suggesting that these CYPs may have critical roles, not only in elimination of endobiotic signalling molecules, but also in their production.”

Honkakoski, P. et. al. Regulation of cytochrome P450 (CYP) genes by nuclear receptors. Biochem J. 2000;347:321-337.

Factors Affecting Phase 1 and Phase 2 Detoxification

The two principle phases of biotransformation are susceptible to induction and/or inhibition by two major factors;

1. Gene polymorphisms leading variable enzyme action and slow and fast metabolisers

2. Environmental factors – both exogenous and endogenous

Phase 2 Detoxification

Phase II enzymes

“The induction of phase II enzymes is considered an important mechanism of protection against chemical stress and carcinogenesis.”Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proc. Nat. Acad. Sci. USA.

1990;87:6258-6262

Phase 2 Detoxification Processes

•Sulphation•Glucuronidation•Glutathionation•Acetylation•Methylation•Glycination

GSTs ARE THE MAJOR PHASE II ENZYMES

“The glutathione transferases (GST’s: also known as glutathione-S-transferases) are major phase II detoxification enzymes found mainly in the cytosol”


Glutathione transferase

“The primary defence of nature against electrophiles occurs by glutathione transferase (GST) catalysed conjugation to glutathione.”

Rinaldi, R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metab Disp. 2002;30:1053-

1058

Glutathione transferase

The glutathione S-transferases (GST) belong to a group of xenobiotic metabolising phase II enzymes that function as intracellular detoxification systems of mutagens, carcinogens, and other toxic compounds

Friling, R. et. al. Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-

responsive element. Proc Nat Acad Sci 1990;87:6258-6262

GST LEVELS DECREASE PROCARCINOGENS

“it is well documented that the proportion of reactive benzo(a)pyrene diol epoxides reacting with DNA in a cellular system is directly related to the amount and nature of glutathione transferases present.”

Rinaldi R. Reactive intermediates and the dynamics of glutathione transferases. Drug Metabolism and Disposition 2002;30(10):1053-58

Prevalence of GSTM1 & GSTT1 Polymorphisms

The range of GSTM1 & GSTT1 null genotype frequencies range from 40% -50% and from 10%-65% in Western and Asian countries, respectively.

Lin J et al. Glutathione S-Transferase M1 and T1 genotypes and

endometriosis risk: a case controlled study. Chin Med J 2003;116(5):777-780

GSTM1 & GSTT1 polymorphisms increase environmental disease

risk“Both GSTM1 and GSTT1 genetic polymorphisms have been demonstrated to affect susceptibility to various cancers, and may be considered as risk modifiers for various environmentally induced diseases.”

Jun, L. et. al. Glutathione-S-transferase M1 and T1 genotypes and endometriosis risk: a case controlled study. Chin Med J 2003;116(5):777-780

PHASE II ENZYME DEFICIENCY IN

ENDOMETRIOSIS“We suggest the involvement of both NAT2

(acetylation) and GSTM1 (glutathione conjugation) detoxification system genes in the pathogenesis of endometriosis and the possible impact of NAT2 gene polymorphism in the development of different forms of this disease.”

Baranova, H. Possible involvement of arylamine N-acetyltransferase 2, glutathione-s-transferases M1 and T1 genes in the development of endometriosis. Mol Hum Reprod 1999;5(7):636-41

grapefruit

GRAPEFRUIT JUICE DOWNREGULATES CYP3A4 IN THE SMALL INTESTINE

“the effect of grapefruit juice on oral felodipine kinetics is its selective down-regulation of CYP3A4 in the small intestine”

Lown K et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A4 protein expression. J Clin Invest 1997;99: 2545-53

GRAPEFRUIT JUICE ALTERS DRUG METABOLISM

“A single glass of grapefruit juice has been shown to significantly increase the oral availability of a variety of commonly used medications”

Lown K et al. Grapefruit juice increases felodipine oral availability in humans by decreasing intestinal CYP3A4 protein expression. J Clin Invest 1997;99: 2545-53

Hypericum

HYPERICUM ALTERS PHARMACOKINETICS

“Recent clinical studies demonstrate the hypericum extracts increase the metabolism of various drugs, including combined oral contraceptives, cyclosporin and indinavir.”

Moore, L. St. John’s Wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl. Acad Sci 2000 June 20; 97(13):7500-2

HYPERICUM INDUCES CYP3A4 EXPRESSION

“Treatment of primary human hepatocytes with hypericum extracts or hyperiforin results in a marked induction of CYP3A4 expression.”


HYPERICUM ALTERS PHARMACOKINETICS

“Because CYP3A4 is involved in the oxidative metabolism of 50% of all drugs, our findings provide a molecular mechanism for the interaction of St. John’s wort with drugs and suggest that hypericum extracts are likely to interact with many more drugs than previously had been realised.”


Kava-Kava

Kava-Kava inhibits CYP3A4 activity

“extracts of kava-kava contain various inhibitors of CYP3A4 and are likely to cause drug interactions when administered concomitantly with drugs metabolised predominantly by CYP3A4”Unger M, et. al. Inhibition of cytochrome P450 3A4 by

extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Med. 2002 Dec;68(12):1055-8

Kava-Kava inhibits CYP3A4 activity“Since one case report

described the coma of a woman after simultaneous

ingestion of kava and alprazolam, a substance

known to be metabolised by CYP3A4, an in-vitro-in-vivo

correlation is obvious”Unger M, et. al. Inhibition of cytochrome P450 3A4 by

extracts and kavalactones of Piper methysticum (Kava-Kava). Planta Med. 2002 Dec;68(12):1055-8

Licorice

Liquorice induces CYP activity

“While a single liquorice or glycyrrhizin dose was unable to affect the multienzymatic CYP-system, using both schedules of repeated treatment, either liquorice or glycyrrhizin were able to significantly induce hepatic CYP3A- and, to a lesser extent, 2B1- and 1A2-dependent microsomal monooxygenase activities”

Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci. 1998; 62(6): 571-82

Liquorice induces CYP activity

“These results suggest that the induction of cytochrome P450-dependent activities by the prolonged intake of high liquorice or glycyrrhizin doses, may result in accelerated metabolism of coadministered drugs with important implications for their disposition”

Paolini M, et. al. Effect of licorice and glycyrrhizin on murine liver CYP-dependent monooxygenases. Life Sci 1998; 62(6): 571-82

Echinacea

ECHINACEA: HERB-DRUG INTERACTION

“Echinacea selectively modulates the catalytic activity of CYP3A at hepatic and intestinal sites. Caution should be used when Echinacea is coadministered with drugs dependent on CYP3A or CYP1A2 for their elimination”

Gorski, JC. et al. The effect of Echinacea (Echinacea purpurea root) on cytochrome P450 avtivity in vivo. Clin Pharmacol Ther 2004; 75: 89-100

Echinacea Herb - Drug Interaction

Echinacea dosing significantly reduced the oral clearance of the CYP1A2 probe caffeine by 27%

There is considerable interindividual variability in this interaction, with 2 individuals showing a greater than 50% reduction in oral clearance.

Gorski JC. Et al. The effect of Echinacea (Echinacea purpurea root) on cyochrome P450 activity in vivo

Heavy Metals

METHYL MERCURY IS TOXIC TO BOTH FOETAL

AND ADULT BRAINS“The neurotoxic effects of methylmercury

(meHg) have been demonstrated in both human and animal studies. Both adult and foetal brains are susceptible to the effects of meHg toxicity.”

Yokoo, E. et al Low level methylmercury exposure affects neuropsychological function in adults. Environmental Health: A Global

Access Science Source 2003;2:8: 1-11

METHYLMERCURY EXPOSURE AFFECTS MENTAL FUNCTION

“adults exposed to meHg may be at risk for deficits in neurocognitive function. The functions disrupted in adults, namely attention, fine motor function and verbal memory, are similar….reported in children with prenatal exposures”

Yokoo, E. et al Low level methylmercury exposure affects neuropsychological function in adults. Environmental Health: A Global Access Science Source 2003; 2:8: 1-11

NICKEL IS A MAJOR ENVIRONMENTAL TOXIN

“Nickel, a major environmental pollutant, is known for its clastogenic, toxic and carcinogenic potentials.

Ahmed S. et al. Ellagic acid ameliorates nickel induced biochemical alterations: diminution of oxidative stress. Hum Exp Toxicol. 1999 Nov;18(11):691-8

Part Two

Improving Biotransformation

Endogenous Toxins: Gut Toxicity

The Human Gut has the Largest Antigenic Load

Over the course of a lifetime, the gastrointestinal tract processes more than 25 tons of food, which represents the largest load of antigens and xenobiotics confronting the human body.

Liska D. The detoxification enzyme systems. Alternative Medicine Review 1998;3(3):187-198

INTESTINAL HEALTH OPTIMISES

DETOXIFICATION“about 25% of detoxification and removal

of toxins occurs in the intestine, which is significant not only in the amount of activity but also because once toxins are deactivated in the intestines they never enter the body.”

Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct 2002

The Gut is a Biotransformational

SystemThe GIT is the second major site in the body

for detoxification. Detoxification enzymes such as Cyp3A4 and the antiporter activities have been found in high concentrations at the tip of the villi in the intestine.

Adequate first pass metabolism of xenobiotics by the GIT requires gut mucosa integrity


Intestinal Permeability Increases Xenobiotic Load

Compromised barrier function of the mucosa will easily allow xenobiotic to transit into the circulation without opportunity for detoxification.


Intestinal permeability increases endotoxin

exposureA potential consequence of increased

intestinal permeability is microbial translocation. Bacteria, fungi, and their toxins may translocate across the mucosal barrier into the bloodstream and cause sepsis. Conditions that might benefit from glutamine supplementation include food allergies and associated conditions, Crohn’s disease, ulcerative colitis and IBS.

Monograph: Glutamine. Alternative medicine review. 2001;6(4)

Anti-microbials

Berberis is a potent antimicrobial

Berberine extracts and decoctions have demonstrated significant antimicrobial activity against a variety of organisms including bacteria, viruses, fungi, protozoans, Helminths, and Chlamydia. Currently, the predominant clinical uses of berberine include bacterial diarrhoea, intestinal parasite infections, and ocular trachoma infections.

Berberine. Altern Med Rev 2000;5(2):175-7

BerberineSpares glutathione and induces a high

level of DNA repair synthesis.Powerful hepatoprotectiveHwang JM. Inhibitory effect of berberine on tert-butyl hydroperoxide induced

oxidative damage in rat liver. ArchToxicol2002 Nov;76(11):664-70.

Reduces hepatic damage.Janbaz KH.Studies on preventive and curative effects of berberine on

chemical induced hepatotoxicity in rodents. Fitoterapia. 2000Feb; 71(1):25-33

Protects against chemical carcinogenesisAnis KV.Inhibition of chemicalcarcinogenesis by berberine in rats and mice. J

Pharm Pharmacol. 2001 May;53(5):763-8

Chinese wormwood is antiparasitic

Artemisinin and its derivatives are a potent new class of antimalarials, originated from Artemisia annua, L. The clinical efficacy of these drugs is characterised by an almost immediate onset and rapid reduction of parasitaemia. Their efficacy is high in such areas as well where multidrug-resistance is rampant.

Balint GA. Artemisinin and its derivatives: an important new class of antimalarial agents. Pharmacol Ther 2001;90(2-3):261-

Grapefruit-seed is antimicrobial

Recent testimonials report grapefruit-seed extract to be effective against more than 800 bacterial and viral strains, 100 strains of fungus, and a large number of single and multicelled parasites.

CONCLUSIONS: The initial data shows grapefruit-seed extract to have antimicrobial properties against a wide range of gram-negative and gram-positive organisms at dilutions found to be safe.

Heggers JP, et. al. The effectiveness of processed grapefruit-seed extract as an antibacterial agent: II. Mechanism of action and in

vitro toxicity J Altern Complement Med 2002;8(3):333-40

Colostrum protects against gut pathogens

“Oligosaccharides and glycoconjugates are some of the most important bioactive components in milk. Their primary role seems to be in providing protection against pathogens by acting as competitive inhibitors for the binding sites on the epithelial surfaces of the intestine. Evidence is also available to support the role of some of these components as growth promoters for genera of beneficial microflora of the colon.”Gopal PK, Gill HS. Oligosaccharides and glycoconjugates in bovine milk and

colostrum. Br J Nutr 2000:84(Suppl 1):S69-74

Colostrum Prevents Endotoxinaemia

“Prophylactic pre-operative oral colostrum shows significantly lower levels of endotoxin and endotoxin neutralising capacity compared to placebo. This suggests a stabilisation of gut barrier during abdominal surgery.”

Bolke E, et al Preoperative oral application of immunoglobulin-enriched colostrum milk and mediator response during abdominal surgery. Shock. 2002 Jan;17(1):9-

12.

Colostrum Neutralises Bacterial Toxins

“An immunoglobulin preparation for oral use was prepared from pooled bovine colostrum: high antibacterial antibody titres, a high capacity for the neutralisation of bacterial toxins, well tolerated, highly effective in the treatment of severe diarrhoea.”

Stephan W, Dichtelmuller H, Lissner R. Antibodies from colostrum in oral immunotherapy. J Clin Chem Clin Biochem. 1990 Jan;28(1):19-23

Colostrum Protects Gut Mucosa

“We examined whether colostrum could reduce the rise in gut permeability caused by NSAIDs in volunteers and patients taking NSAIDs for clinical reasons. In volunteers, indomethacin caused a 3-fold increase in gut permeability in the control arm, whereas no significant increase in permeability was seen when colostrum was co-administered.”

Playford RJ, et. al. Co-administration of the health food supplement, bovine

colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability. Clin Sci (Lond). 2001 Jun;100(6):627-33.

Colostrum Is Effective in Refractory Diarrhoea

25 patients infected with the human immunodeficiency virus with chronic refractory diarrhoea and either confirmed cryptosporidiosis or absence of demonstrable pathogenic organisms were treated with a daily oral dose of 10 g of an immunoglobulin preparation from bovine colostrum over a period of 10 days.

Colostrum is Effective in Refractory Diarrhoea

Treatment of refractory diarrhoea with immunoglobulins from bovine colostrum constitutes an important therapeutic approach and led to complete (40%) or partial (24%) remission of diarrhoea in 64% of the patients described here.

Plettenberg A, et. al. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhoea. Clin Investig. 1993 Jan;71(1):42-5

Probiotics

PROBIOTICS IMPROVE GUT DETOXIFICATION

“The cells of lactic acid bacteria bind the various fried-food mutagens and remove them from the intestine”

Rao CV, et. al. Prevention of colonic preneoplastic lesions by the probiotic Lactobacillus acidophilus NCFM in F344 rats. Int J

Oncology 1999;14:939-44

“The NCFM strain of acidophilus adheres to Caco-2 and mucus-secreting HT-29 cell culture systems, produces antimicrobial compounds… NCFM survives gastrointestinal tract transit in both healthy and diseased populations. NCFM inhibits aberrant crypt formation in mutagenised rats, indicative of activity that could decrease the risk of colon cancer. A blend of probiotic strains containing NCFM decreased the incidence of pediatric diarrhoea. NCFM led to a significant decrease in levels of toxic amines in the blood of dialysis patients with small bowel bacterial over-growth. NCFM may facilitate lactose digestion in lactose-intolerant subjects.”

J Dairy Sci 2001;84:319-331J Dairy Sci 2001;84:319-331

L. ACIDOPHILUS IMPROVES GUT

BIOTRANSFORMATION“L. acidophilus have been shown to reduce

the counts of colonic putrefactive bacteria as indicated by faecal bacterial β-glucuronidase which is believed to be largely responsible for the hydrolysis of glucuronide conjugates in the colon and thus important in the generation of toxic and putative carcinogenic agents.”

Rao CV, et. al. Prevention of colonic preneoplastic lesions by the probiotic Lactobacillus acidophilus NCFM in F344 rats. Int J Oncology 1999;14:939-44

LBA LOWERS SYSTEMIC ENDOTOXIN LEVELS

“we found that giving oral LBA could reduce the blood level of dimethylamine by about 31%, nitrosodimethylamine by 53% and improve nutritional status as measured by modest increases in weight gain, caloric intake and anthropometric measurements”

Dunn S. Effect of oral administration of freeze-dried Lactobacillus acidophilus on small bowel bacterial overgrowth in patients with end stage kidney disease: reducing uraemic toxins and improving nutrition. Int Dairy J 1998;8:545-53

L. acidophilus Reduces Large Bowel Tumour

PromotersAddition of L. acidophilus supplements to the diet reduces β-glucuronidase and nitroreductase in rats and humans.

These interstitial alterations appear to reduce the capacity of the intestinal flora to catalyse the formation of carcinogens and / or the promotional factors involved in the chemical induction of large bowel tumours.

Goldin BR. The Effect of oral administration on Lactobacillus and antibiotics on intestinal bacterial activity and chemical induction of large bowel tumours. Symposium: genetics, physiology and utility of Lactobacilli

Probiotics Reduce Atopic Disease

Probiotics provide a non-pathogenic challenge to the Th1 immune system, which has an inhibitory effect on atopy.

Probiotics have also been shown to reverse increased intestinal permeability and to reduce antigen load in the gut by degrading and modifying potentially harmful macromolecules.

Kalliomaki M, et al. Pandemic of atopic diseases - a lack of microbial exposure in early infancy. Curr Drug Targets Infect Disord 2002 Sep;2(3):193-9

L. acidophilus induces Th1 immune cytokines

“A significant induction of IL-2 and IL-12 was observed with L. acidophilus. These effects were dose dependent.”

Thus acidophilus induces Th1 cells via the induction of IL-12 and IL-2.

Perdigon G, et. al. Interaction of lactic acid bacteria with the gut immune system. Eur J Clin Nutr 2002;56:S21-6

Acidophilus prevents Th2 skewing after antibiotic

therapy“These results suggest that adequate

probiotic intervention after antibiotic treatment may improve the intestinal ecosystem, and thereby prevent the Th2-shifted immunity induced by neonatal antibiotic use.”Sudo N et al. An oral introduction of intestinal bacteria prevents the

development of a long-term Th2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy

2002;32(7):1112-6

Probiotics Normalise Th1/Th2 by:

- normalising intestinal permeability - balancing gut microecology, - improving immunological defence barrier (IgA) of the intestine, - alleviating intestinal inflammation- down regulation of proinflammatory cytokines characteristic of local and systemic allergic inflammation.Miraglia del Giudice M et al. Probiotics and atopic dermatitis. A new strategy in atopic dermatitis. Dig Liver Dis 2002;34:S68-71

Probiotics

L. plantarum 299v Improves Immune ControlThe strain L. plantarum 299v originates

from the human intestinal mucosa and has been shown to decrease bacterial translocation, improve mucosal status, improve liver status, improve the immunologic status of the mucosa, and reduce mucosal inflammation.

Molin G. Probiotics in foods not containing milk or milk constituents, with special reference to Lactobacillus plantarum 299v. Am J Clin Nutr 2001 Feb;73(2 Suppl):380S-385S

L. plantarum 299v Helps Healing of the Gut

“In our study, administration of L. plantarum 299v seems to reduce the inflammatory reaction and increase the deposition of collagen at the healing wound, and thus help to restore the continuity and healing of the anastomotic part. Thus administration of lactobacilli may modulate intestinal injury following radiation and have some impact on cytoprotection.”

Administration of Lactobacillus plantarum 299v reduces side-effects of external radiation on colon anastomotic healing in an experimental model. Colorectal Disease 2001;3(4):245

L. plantarum 299V reduces Ulcerative colitis in unresponsive

patientsNineteen patients with ulcerative colitis who had

remained unresponsive to 4 weeks of treatment with corticosteroid and 5-aminosalyclic acid therapy received L. plantarum 299v or placebo. Seven of the 10 patients who received 299v solution achieved clinical and colonoscopic remission. One had a partial response and two failed to respond at all. In the placebo group (n = 9), no patient achieved remission and only two had a partial improvement.

Kordecki H, Niedzielin K: New conception in the treatment of ulcerative colitis: Probiotics as a modification of the microflora of the colon (Abstr). IN Proceedings of Falk Symposium No. 105, 1998,

45

L. plantarum 299v Improves IBS

Forty patients were trialled in a controlled, double-blind randomised study to assess the effect of 299v on IBS. They received either Lactobacillus plantarum 299v (20 patients) or placebo (20 patients) over a period of 4 weeks.

RESULTS: “All patients treated with Lactobacillus plantarum 299V reported resolution of their abdominal pain.”

Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomised study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol 2001 Oct;13(10):1143-7

Treatment Outcome of IBS Patients with L plantarum (299v) over 4 Weeks

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120

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Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol 2001 Oct;13(10):1143-7

L. Plantarum 299v Reduces Cardiovascular Risk Factors

Studies show in hypercholesterolaemic patients that supplementation with the probiotic bacteria Lactobacillus plantarum 299v significantly lowers concentrations of LDL cholesterol and fibrinogen. The short-chain fatty acids formed in the human colon by the bacterial fermentation of fibre may have an anti-inflammatory effect, may reduce insulin production, and may improve lipid metabolism. Naruszewicz M, et al. Effect of lactobacillus plantarum 299v on cardiovascular disease risk factors in smokers. Am J Clin Nutr 2002;76(6):1249-55

L.plantarum (299v)

L. plantarum Reduces Cardiovascular Risk Factors in

smokers within 6 weeks of treatment

IL-6

Monocyte

Adhesion

Isoprostanes Fibrinogen

Leptin

BPLDL Cholesterol

Naruszewicz M et al. Effect of L.plantarum 299v on Cardiovascular disease risk factors in smokers Am J Clin Nutr 2002;76(6):1249-55

Glutamine Reduces Gut Inflammation

“Glutamine reduces pro-inflammatory cytokine production by human intestinal mucosa, probably by a post-transcriptional pathway. Glutamine could be useful to modulate inflammatory conditions with imbalanced cytokine production.”

Coeffier M, et. al. Influence of glutamine on cytokine production by human gut in vitro. Cytokine 2001;13(3):148-54

Glutamine Maintains Gut Health

“Glutamine and glutamine supplementation appear to be important for the normal maintenance of intestinal morphology and function, intestinal adaptation following resection, and prevention of clinical infection related to bacterial translocation.”

Buchman AL. Glutamine for the gut: mystical properties or an ordinary amino acid? Curr Gastroenterol Rep 1999 Oct;1(5):417-23

Effects of Glutamine

• Glutamine Reduces Gut Inflammation

• Glutamine Maintains Gut Health• Glutamine Improves Gut Function

Licorice

Deglycyrrhizinated liquorice protects gastric mucosa

Gastric mucosal damage induced by oral administration of 60mg of aspirin is reduced by simultaneous administration of 100-500mg deglycyrrhizinated liquorice. Human faecal blood loss induced by 975mg aspirin three times a day, was less when 350mg of deglycyrrhizinated liquorice was administered with each dose of aspirin.

Rees WD, et. al. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scand J Gastroenterol 1979;14(5):605-7.

Deglycyrrhizinated liquorice effective for

gastric ulcersIn a trial of DGL for the treatment of

peptic ulcer, it was found to be as effective as cimetidine (Tagamet).

Morgan AG, et. al. Comparison between cimetidine and Caved-S in the treatment of gastric ulceration, and subsequent maintenance therapy. Gut 1982;23:545-551.

Another trial published in the Lancet the same year found DGL to be as effective as ranitidine (Zantac).

Glick L. Deglycyrrhizinated liquorice for peptic ulcer. Lancet 1982;9:817.

Aloe vera a powerful anti-inflammatory

“Aloe vera was active in all models of inflammation. Oral activity of Aloe vera was demonstrated to be dependent on the presence of anthraquinones. The various irritant-induced oedema models provided a broad spectrum of anti-inflammatory activity for Aloe veraDavis RH, et. al. Anti-inflammatory activity of Aloe vera against a spectrum of irritants. J Am Podiatr Med Assoc. 1989;79(6):263-276

Aloe is a safe and effective laxative

“Aloe is a potent laxative due to its anthraquinone glycosides content which act directly on the lining of the intestines to stimulate peristalsis and which increase water absorption in the intestines”

Roberts AJ, et. al. Nutraceuticals: the Complete Encyclopedia of Supplements, Herbs, Vitamins and Healing Foods. Berkely Publishing

Group. New York, USA. 2001:93

Liver Detoxification

macronutrients

PROTEIN REQUIRED FOR DETOXIFICATION

“Hepatic mixed-function oxidase activities increase with increase in dietary proteins. In rodents fed with high protein diet, acute oral toxicity of a number of pesticides (lindane, malathione, DDT, carbaryl and captan) have been shown to be reduced.”

“Oxidative drug metabolism (phase I reactions) of antipyrine, theophylline, propranolol and other drugs in humans is increased with protein rich diet.”

PROTEIN CONSUMPTION SUPPORTS PHASE II

“High quality protein is a good source of methionine, cysteine, glutamine and glycine in a form that provides high absorption; these amino acids can be used to generate sulphation, glutathione and amino acid conjugation cofactors.”

Liska D, et. al. From the Townsend Letter for Doctors and Patients. Oct 2002

PHASE II INDUCTION ELEVATES GLUTATHIONE

“The induction of these (phase II) enzymes is accompanied by elevations of intracellular GSH levels which augment cellular antioxidant protection”

Prestera T. Chemical and molecular regulation of enzymes that detoxify carcinogen. Proc Natl Acad. Sci 1993;90:2965-69

ADEQUATE PHASE II ACTIVITY PROMOTES

EFFECTIVE BIOTRANSFORMATION

“In general, increases in phase I combined with increases in phase II metabolism will result in faster clearance and reduced carcinogenicity of ingested procarcinogens such as polycyclic hydrocarbons”

Ronis M. Altered expression and glucocorticoid-inducibility of hepatic CYP3A and CYP2B enzymes in male rats fed diets containing soy protein isolate. J Nutr

1999;129:1958-65

IMPORTANCE OF PHASE II INDUCERS

“a voluminous literature now supports the view that induction of phase II enzymes is an important and sufficient mechanism for achieving protection against the toxic and neoplastic effects of many carcinogens”

Talalay P, et. al. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 2001;131(S):3027S-33S

Silymarin

SILYMARIN AS A HEPATOPROTECTANT

“Milk thistle is commonly used as a hepatoprotectant. Silymarin, the major component of milk thistle, is reported to inhibit nitric oxide production, is a potent free radical scavenger and prevents lipid peroxidation,”Venkataramanan, et. al. Milk thistle, a herbal supplement,

decreases the activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte

cultures. Drug Metabolism and Disposition 2000;28(11):1270-73

SILYMARIN AS A HEPATOPROTECTANT

“Silymarin enhances the activity of hepatocyte RNA polymerase, and complexes toxic free iron. Silymarin/silybin is reported to protect the liver against several hepatotoxins in rats.”

Venkataramanan, et. al. Milk thistle, a herbal supplement, decreases the activity of CYP 3A4 and uridine

diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-73

SILYMARIN REDUCES CYP3A4

“Treatment with silymarin (0.1 and 0.25 mM) significantly reduced the activity of CYP 3A4 enzyme (by 50 and 100%, respectively)”


diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-73

SILYMARIN MODULATES BIOTRANSFORMATION

“Our studies clearly document the potential of silymarin to inhibit the metabolism of substrates of CYP 3A4 and UGT1A6/9 in humans.”


diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-

73

Silybum increases hepatic glutathione

Silybum has also received attention for its ability to increase the intracellular concentration of glutathione in the liver and prevent cellular damage by toxins.

Scanlan N. Compromised hepatic detoxification in companion animals and it’s correction via nutritional supplementation

and modified fasting. Alternative Medicine Review. 2001;6(suppl)s24-s37.

Silymarin improves alcoholic liver disease

“histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease”Saller R, et. al. The use of silymarin in the treatment of liver diseases.

Drugs. 2001; 61(14):2035-63

BIFUNCTIONAL EFFECTS OF SILYMARIN

• Inhibits phase I enzymes (CYP3A4)• Increases glutathione peroxidase• Induces glutathione transferase• Increases serum glutathione• Improve liver function in toxic exposure• Strong antioxidant activityLiska D. et al. From the Townsend Letter for Doctors and Patients. Oct

2002

Glycine

GLYCINE ATTENUATES TOXIN-INDUCED HEPATIC

INJURY“Destruction of Kupffer cells with

gadolinium chloride as well as Kupffer cell inactivation with dietary glycine, diminishes stellate cell α-smooth muscle actin expression and collagen production, most likely by preventing the release of profibrogenic cytokines from Kupffer cells.”

GLYCINE PREVENTS LIVER DAMAGE

“In a rat model of endotoxin shock, dietary supplementation with glycine blunted liver and lung injury and improved survival. Furthermore, dietary glycine prevented necrosis and inflammation that developed early during chronic intragastric ethanol administration.”

Rivera C. et al. Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 2001;281:G200-7

GLYCINE PREVENTS LIVER DAMAGE

“glycine may be an effective therapy against liver damage, including injury caused by chronic exposure to alcohol. The mechanism of protection against injury afforded by glycine most likely involves the inactivation of Kupffer cells.”

Rivera C. et al. Attenuation of CCl4-induced hepatic fibrosis by GdCl3 treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 2001; 281:G200-7

Glycine conjugation is dependent on glycine

supply“It is concluded that the activity of glycine cleavage system is an important determinant of glycine supply and, thereby, the capacity of glycine conjugation of xenobiotics”

Gregus Z, et. al. Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage system.

Xenobiotica. 1993 Feb; 23(2): 141-53

Glycine conjugation is dependent on glycine

supply“The normal endogenous glycine supply permits glycine conjugation only at an approximate half-maximal rate”

Gregus Z, et. al. Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage

system. Xenobiotica. 1993 Feb; 23(2): 141-53

Glycine reduces hepatic injury

“Importantly, dietary glycine (5%) largely blocked chronic CsA-induced activation of Kupffer cells, blunted production of PGE(2), prevented the hypermetabolic state, and minimised tissue hypoxia”

Zhong Z, et. al. Cyclosporin A causes a hypermetabolic state and hypoxia in the liver: prevention by dietary glycine. J Pharmacol Exp

Ther. 2001 Dec; 299(3): 858-65

Glycine attenuates hepatic injury

“Dietary glycine is protective in rat models against endotoxemia, liver ischemia-reperfusion, and liver transplantation, most likely by inactivating the Kupffer cell via this newly identified glycine-gated chloride channel”

Wheeler MD, et. al. Glycine: a new anti-inflammatory immunonutrient. Cell Mol Life Sci. 1999 Nov 30;56(9-10):843-56.

Glycine attenuates hepatic injury

“Moreover, dietary glycine is protective in the kidney against cyclosporin A toxicity and ischemia-reperfusion injury. Glycine may be useful clinically for the treatment of sepsis, adult respiratory distress syndrome, arthritis, and other diseases with an inflammatory component”

Wheeler MD, et. al. Glycine: a new anti-inflammatory immunonutrient. Cell Mol Life Sci. 1999 Nov 30;56(9-10):843-56.

Calcium-D-Glucarate

CALCIUM-D-GLUCARATE INHIBITS BETA-

GLUCURONIDASE

“Supplementation of calcium-D-glucarate has been shown to inhibit beta-glucuronidase, an enzyme produced by colonic microflora and involved in phase II liver detoxification.”

Calcium-D-Glucarate (Monograph). Alt Med Rev 2002 Aug

CALCIUM-D-GLUCARATE IMPROVES OESTROGEN

DETOXIFICATION“Calcium-D-glucarate’s inhibition of

beta-glucuronidase activity allows the body to excrete hormones such as oestrogen before they can become reabsorbed.”


CALCIUM-D-GLUCARATE INCREASES

GLUCURONIDATION

“Calcium-d-glucarate’s detoxifying and anticarcinogenic properties are attributed to its ability to increase glucuronidation and excretion of potentially toxic compounds.”


CALCIUM-D-GLUCARATE IMPROVES OESTROGEN

DETOXIFICATION“Because many breast cancers are

oestrogen-dependent, calcium-D-glucarate’s ability to affect oestrogen and other hormone levels has led to Phase I clinical trials at several major cancer centres in the U.S.”


GLUCURONIDATION• Chemical carcinogens• Steroid hormones• Lipid-soluble toxins During phase II detoxification, these

toxins are conjugated with glucuronic acid in the liver (glucuronidation), and excreted through the biliary tract.


PHYTONUTRIENTS Regulate Phase 1 Detox

“They have the capacity to inhibit certain enzymes (CYP) at high concentrations of the compound and to activate moderately the same enzyme at lower concentrations”

Lampe J. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr 1999;70(suppl):475S-490S

PHYTONUTRIENTS Regulate Phase 1 Detox

“This points to a complex association between consumption of a typical diet of various vegetables and biotransformation enzyme activities in humans”

Lampe J. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P4501A2 activity in humans: changes to caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000;21(6):1157-62

Increasing Phase 2 Improves Detoxification

Commonly, the glutathione S-transferase and glucuronyl transferases are induced by bi-functional inducers.

In general, this increase in Phase II supports better detoxification in the individual and helps to promote and maintain a healthy balance between Phase I and Phase II activities.

Liska D. The Detoxification Enzyme Systems. Alternative Medicine Review. 1998;3(3): 187-198

Bi-functional support improves detoxification and

symptomsIn organisms where Phase I enzymes are

high but Phase II enzymes are low, there is a great risk of a toxic episode.

Scanlan N. Compromised hepatic detoxification in companion animals and it’s correction via nutritional supplementation and

modified fasting. Alternative Medicine Review. 2001;Vol6(suppl):S24-S37.

Cruciferous vegetables reduce cancer risk

The unique effectiveness of cruciferous vegetables to protect against neoplastic disease is attributed to the fact that they are the richest sources of glucosinolates in the human diet.

Brassica species can contain a dozen different glucosinolates… a lower-risk enzyme profile

Lampe J, Peterson S. Brassica, biotransformation and cancer risk: Genetic polymorphisms alter the preventive effects of cruciferous vegetables. American society for nutritional sciences, June 2002.

CRUCIFEROUS VEGETABLES ARE BIFUNCTIONAL

MODULATORS“For example, compounds in cruciferous

vegetables can alter drug metabolism by both inhibiting and inducing certain CYP’s and possibly by inducing select conjugating enzymes.”

Lampe J. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr 1999;70(suppl):475S-490S

BROCCOLI AND WATERCRESS INHIBIT

CYP3A4“The inhibition (of) CYP3A4 (by PEITC)

was a mixed type of competitive and non-competitive inhibition”

Nakajima M. Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate. Drug Metabolism and Disposition 2001;29(8):1110-13

SULFORAPHANE: THE MOST POTENT PHASE II

INDUCER“Sulforaphane is an extremely potent

inducer of phase II enzymes, perhaps the most potent naturally occurring inducer described to date.”

Talalay P et al. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 2001;131(S):3027S-33S

Glucosinolates are Converted to

Isothiocyonates“Crucifers that are widely consumed are

especially rich in glucosinolates, which are converted by plant myrosinase and gastrointestinal microflora to isothiocyanates”

Talalay P et al. Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism. J Nutr 2001;131(S):3027S-33S

SULFORAPHANE OVERCOMES ANTIBIOTIC

RESISTANCE“H. pylori is now recognised as one of the

most prevalent human pathogens in the world...it is difficult to eradicate in 15-20% of individuals by antibiotic therapy, which is now recommended for infected patients with gastric or duodenal ulcers or gastric mucosa-associated lymphoid tissue lymphoma”

Fahey, J. Sulforophane inhibits extracellular, intracelllular, and antibiotic resistant strains of helicobacter pylori and prevents benzo(a)pyrene-induced stomach tumours. PNAS 2002 May;99(11):7610-15

SULFORAPHANE OVERCOMES ANTIBIOTIC

RESISTANCE“sulforaphane.. an isothiocyanate abundant

as its glucosinolate precursor in certain varieties of broccoli and broccoli sprouts, is a potent bacteriostatic agent against 3 reference strains and 45 clinical isolates of H. pylori, irrespective of their resistance to conventional antibiotics.

Fahey, J. Sulforophane inhibits extracellular, intracelllular, and antibiotic resistant strains of helicobacter pylori and prevents benzo(a)pyrene-induced stomach

tumours. PNAS 2002 May;99(11):7610-15

Bi-functional effects of Brassica Family

• Decreases CYP3A4 activity• Up-regulates CYP1A2• Induces glutathione-S-transferase• Up-regulates glutathione• Induces quinone reductase• Induces glucuronidation

Effects of Sulforaphane• Most potent phase II enzyme inducer• Bacteriostatic (H. pylori, other

pathogens)• Induces glutathione-S-transferase• Up-regulates glutathione• Induces quinone reductase• Induces glucuronidation

Watercress

WATERCRESS IMPROVES BIOTRANSFORMATION

“Phenethyl isothiocyanate can inhibit metabolism of 4-(methylnitrosamin)-1-(3-pyridyl)-1-butanone a tobacco-specific lung carcinogen. …Watercress consumption increased urinary excretion of detoxified metabolites by 30%.”

Lampe J. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr

1999;70(suppl):475S-490S

Watercress reduces DNA damage

Treatment of Hep G2 cells with small amounts of watercress or garden cress juice and benzo(a)pyrene reduced the genotoxic effect of the benzo(a)pyrene in a dose dependent manner.

Findings show that garden and water cress juices are highly protective against B(a)P - induced DNA damage in human derived cells.

Kassie F. Effects of garden and water cress juices and their constituents, benzyl and phenethyl isothiocyanates, towards

benzo(a)pyrene-induced DNA damage: a model study with the single cell gel electrophoresis / Hep G2 assay. Chemico-Biological

Interactions 2003;142:285 - 296.

WATERCRESS INHIBITS CYP2E1 ACTIVITY

“results show that a single ingestion of watercress inhibits the hydroxylation of chlorzoxazone, an in vivo probe for CYP2E1 (in human volunteers)”

Leclercq I et al. Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by single ingestion of watercress. Clin

Pharmacol Ther 1998;64(2):144-9

BIFUNCTIONAL EFFECTS OF WATERCRESS

• Selective inhibition of phase I• Induction of phase II glucuronosyl

transferases• Induction of glutathione-S-

transferases

Liska D. et al. From the Townsend Letter for Doctors and Patients. Oct 2002

Green Tea

Green tea decreases CYP activity

“Catechins also inhibited the oxidations of typical substrates catalysed by human CYPs, namely ethoxycoumarin O-deethylation by CYP1A1, ethoxyresorufin O-deethylation by CYP1A2 and midazolam 1'-hydroxylation by CYP3A4”

Muto S, et. al. Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450. Mutat

Res 2001;479(1-2):197-206

Green tea decreases CYP activity

“Epicatechin gallate inhibited other forms of human CYP such as CYP2A6, CYP2C19 and CYP2E1, indicating the non-specific inhibitory effects of epicatechin gallate toward human CYPs”

Muto S, et. al. Inhibition by green tea catechins of metabolic activation of procarcinogens by human cytochrome P450.

Mutat Res 2001;479(1-2):197-206

Green tea maintains bowel detoxification

The reduction of such faecal parameters as moisture, pH, ammonia, sulphide, and ORP by tea catechin administration indicated very favourable improvements of the subjects bowel conditions.

Goto K et al. The effects of tea catechins on faecal conditions of elderly residents in a long term care facility. J Nutr Sci Vitaminol 1999;45(1):135-41

Green Tea Induces Phase II Activity

Induction of phase II enzymes, glutathione-S-transferase and quinone reductase, were enhanced by nearly all tea fractions, while glutathione was induced by only a few fractions.

Steele VE. Comparative chemopreventative mechanisms of green tea, black tea and selected polyphenol extracts measured by in vitro

bioassays. Carcinogenesis 2000;21(1):63-67

Green Tea Reduces Cancer Incidence

Cancers reduced by Green Tea consumption:• breast• colon and rectum• gall bladder and liver• lung and nasopharynx• pancreas• stomach • uterus

Green Tea Inhibits Free Radical Formation

Most tea fractions inhibited free radical formation in human cells as measured by nine in vitro assays.

Steele VE. Comparative chemopreventative mechanisms of green tea, black tea and selected polyphenol extracts measured by in vitro

bioassays. Carcinogenesis 2000;21(1):63-67

BIFUNCTIONAL EFFECTS OF CATECHINS

• Modulation of phase I detoxification• Induction of phase II glucuronidation• Enhance glutathione conjugation

enzymes• Anticarcinogenic• Antimutagenic• AntioxidantLiska D. et al. From the Townsend Letter for Doctors and Patients. Oct 2002

Artichoke

Artichoke improves detoxification

The artichoke extracts did not affect the cellular level of glutathione (GSH) but diminished the loss of total GSH and the cellular leakage of GSS resulting from exposure to tert-butylhydroperoxide.

Gebhardt R. Antioxidative and protective properties of extracts from leaves of the articholke (Cynara scolymus L.) against hydroperoxide-

induced oxidative stress in cultured rat hepatocytes. Toxicol Appl Pharmacol 1997;144(2):279-86

Artichoke is a powerful hepatoprotectant

These results demonstrate that artichoke extracts have a marked antioxidative and protective potential.

Gebhardt R. Antioxidative and protective properties of extracts from leaves of the articholke ( Cynara scolymus L.) against

hydroperoxide-induced oxidative stress in cultured rat hepatocytes. Toxicol Appl Pharmacol 1997;144(2):279-86

Curcumin

Curcumin inhibits carcinogen bioactivation

“Because CYP1A1 is one of the primary carcinogen-activating enzymes in oral mucosa, the use of curcumin as an oral cavity chemopreventive agent could have significant clinical impact via its ability to inhibit carcinogen bioactivation”Rinaldi, et. al. Curcumin activates the aryl hydrocarbon receptor yet

significantly inhibits (-)-benzo(a)pyrene-7R-trans-7,8-dihydrodiol bioactivation in oral squamous cell carcinoma cells and oral

mucosa. Cancer Res. 2002; 62(19):5451-6

Curcumin Blocks Carcinogen-DNA Adducts

Curcumin has been shown in experimental studies to have anti-inflammatory properties, to prevent tumourigenesis mutagenesis, to block carcinogen - DNA adduct formation, and to inhibit angiogenesis.

Dinkova-Kostova AT. Relation of structure of curcumin analogues to their potencies as inducers of Phase 2 detoxification enzymes..

Carcinogenesis. 1999;20(5 ):911-914

Curcuminoids Induce Phase 2 Activity

Curcumin and a number of naturally occurring and synthetic analogues are phase 2 enzyme inducers, as demonstrated by their ability to elevate the enzyme activity of QR in hepatoma cells. This plays a major role in its chemoprotective and antioxidant activities.Dinkova-Kostova AT. Relation of structure of curcumin analogues to their potencies as inducers of Phase 2 detoxification enzymes.. Carcinogenesis.

1999;20(5 ):911-914

Tumeric reduces endotoxic hepatic injury

“These results demonstrate that curcuminoids are effective in suppressing the hepatic microvascular inflammatory response to LPS and may be a natural

alternative anti-inflammatory substance”

Lukita-Atmadja W, et. al. Effect of curcuminoids as anti-inflammatory agents on the hepatic microvascular response to endotoxin. Shock. 2002

May;17(5):399-403.

Curcumin is a Bifunctional Modulator

• Chemoprotective agent:– elevates activity of phase 2 detoxification

enzymes of xenobiotic metabolism eg, glutathione transferases and NAD(P)H: quinone reductase.

– Inhibits procarcinogen activating Phase 1 enzymes eg, CYP4501A1.

Dinkova-Kostova AT. Relation of structure of curcumin analogues to their potencies as inducers of Phase 2 detoxification enzymes..

Carcinogenesis. 1999;20(5 ):911-914

Limonene

Limonene improves functional

biotransformation“The blocking chemopreventive effects of limonene and other monoterpenes during the initiation phase of mammary carcinogenesis are likely due to the induction of Phase I and Phase II carcinogen-metabolizing enzymes, resulting in carcinogen detoxification”

Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999;129(3):775S-778S


biotransformationIronically, a comparative analysis of DMBA metabolism in control, limonene-treated rats revealed that more of the proximate carcinogen is produced in monoterpene-treated animals than in controls However, these effects are overcome by the induction of glutathione-S-transferase and UDP-glucuronyl transferase by limonene”

Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr. 1999 Mar;129(3):775S-778S


biotransformation“These results correlate well with the

reduction in tumour incidence and multiplicity observed in rats treated with dietary limonene during the initiation phase of DMBA-induced mammary cancer”

Crowell PL. Prevention and therapy of cancer by dietary monoterpenes. J Nutr 1999;129(3):775S-778S

Limonene improves biotransformation

“Dietary D-limonene (1.0% diet for 10 days) maintained liver GSH concentrations at 92% of control values in the paracetamol-challenged mouse without altering GST activity. D-Limonene also increased liver GSH concentration (23%) in mouse fed 1.0% D-limonene alone.”

Reicks MM. Effects of D-limonene on hepatic microsomal monooxygenase activity and paracetamol-induced glutathione

depletion in mouse. Xenobiotica. 1993;23(7):809-19

Limonene improves biotransformation

“D-Limonene, a monoterpenoid constituent of citrus fruit oil, blocks tumour induction by chemical carcinogens in laboratory animals, apparently by preventing bioactivation of procarcinogens and by enhancing conjugation of proximal carcinogenic metabolites.”

Reicks M. Effects of D-limonene on hepatic microsomal monooxygenase activity and paracetamol-induced glutathione

depletion in mouse. Xenobiotica. 1993;23(7):809-19

Limonene and breast cancer

“Monoterpenes are found in the essential oils of many commonly consumed fruits and vegetables. These compounds have been shown to exert chemopreventive and chemotherapeutic activities in mammary tumour models and represent a new class of breast cancer therapeutic agents”

Bardon S, et. al. Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer

cell lines. Nutr Cancer. 1998;32(1):1-7.

.

.

Limonene and breast cancerWe investigated the effects of

limonene and limonene-related monoterpenes on cell growth, cell cycle progression, and expression of cyclin D1 cell cycle-regulatory gene in breast cancer cell lines. Our results revealed that limonene-related monoterpenes caused a dose-dependent inhibition of cell proliferation.”

Bardon S, et. al. Monoterpenes inhibit cell growth, cell cycle progression, and cyclin D1 gene expression in human breast cancer

cell lines. Nutr Cancer. 1998;32(1):1-7.

APIACEOUS VEGETABLES DECREASE CYP1A2

“CYP1A2 activity: Brassica vegetables increased and apiaceous vegetables decreased activity compared with the basal and allium diets. This points to a complex association between consumption of a typical diet of various vegetables and biotransformation enzyme activities in humans”

Lampe J. et al. Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. Carcinogenesis 2000;21(6):1157-62

APIACEOUS VEGETABLES REDUCE PHASE 1

ACTIVITY“Some Rutaceae (eg. citrus fruits) also

contain furanocoumarins and inhibition of CYP3A4 and CYP1A2 activity by grapefruit juice has been attributed in part to the presence of furanocoumarins”


APIACEOUS FAMILY DECREASES CYP ACTIVITY“Certain apiaceous vegetables,

including celery, parsnips and parsley, are significant sources of furanocoumarins, compounds which have been shown to inhibit several human P450s.”


BUPLEURUM IS ANTI-INFLAMMATORY

“Bupleurum falcatum L., (containing) saikosaponins a and d …. had metabolic actions as well as anti-inflammatory actions. These metabolic actions and anti-inflammatory action of saikosaponins may confirm the clinical application of Bupleurum.”

Abe H et al. Protective effect of saikosaponin-d isolated from Bupleurum falcatum L. on CCl4-induced liver injury in the rat. Naunyn Schmiedebergs Arch Pharmacol. 1982 Sep;320(3):266-71

Bupleurum increases bile production

Both aqueous and decoction of Bupleurum have been shown to increase total bile output and bile salt content, indicating cholagogic and choleretic actions.

Chang, H, et. al. Pharmacology and application of Chinese materia medica, Vol 2. World scientific publishing Co. 1987

Bupleurum increases bile production

Oral administration of Bupleurum species to dogs with carbon tetrachloride-induced hepatitis quickly restored to normal the deranged hepatobillary secretion function and chemical composition of bile .

Chang, H, et. al. Pharmacology and application of Chinese materia medica, Vol 2. World scientific publishing Co. 1987

BUPLEURUM REDUCES HEPATIC INJURY

Pretreatment with saikosaponin-d produced a remarkable inhibitory action on acute hepatic injury by CCl4. A significant inhibition of lipid peroxidation induced by an acute dose of CCl4 in the liver of rats pre-treated with saikosaponin-d was also noted”

Abe H et al. Protective effect of saikosaponin-d isolated from Bupleurum falcatum L. on CCl4-induced liver injury in the rat. Naunyn Schmiedebergs

Arch Pharmacol. 1982 Sep;320(3):266-71

Bupleurum exerts anti-hepatitis B activity

Saikosaponins, the main active constituents of Bupleurum spp, have been shown to possess immunomodulatory, hepatoprotective, anti-tumour and anti-viral activities.

Results showed that HBV-transfected human hepatoma cells, cultured with saikosaponin c showed a significantly lower level of HBeAg in culture medium.

Chiang LC, et al. Cytotoxicity and anti-hepatitis B virus activities of saikosaponins from bupleurum species. Planta Med 2003;69:705-709

Barberry

Berberine stimulates bile secretion

“Berberine is an alkaoloid found in a number of clinically-important medicinal plants, including Berberis vulgaris (barberry). Berberines actions include the ablility to stimulate bile secretion and billirubin discharge.”

The activity of berberine may explain the long traditional use of berberis as a cholagouge in the treatment of hepatic disorders.

Bidsall, T, et. al. Berberine: theraputic potential of an alkaloid found in several medicinal plants. Alt Med Rev. 1997;2(2):94-103

Taurine

Bile synthesis requires taurine

For bile acids to be solubilised at physiological pH, it is essential they be conjugated through peptide linkages with either glycine or taurine.

Taurine conjugation of bile acids has a significant effect on the solubility of cholesterol, increasing it’s excretion and reducing serum levels.

Mizushima S. et al. Effects of oral taurine supplementation on lipids and sympathetic nerve tone. Adv Exp Med Biol 1996;403:615-622

Taurine accelerates bile synthesis

The total bile acids concentration in the feces and intestinal contents of rats fed taurine were significantly higher than those in rats fed a control diet.

Taurine accelerated bile acid synthesis and excretion, thereby increasing cholesterol consumption

Kishida T, et al. Increase of bile acids synthesis and excretion caused by taurine administration prevents the ovariectomy-induced increase in cholesterol concentrations in the serum low-density lipoprotein fraction of Wistar rats. J Nutr Biochem. 2003 Jan;14(1):7-16.

Taurine is the preferred bile substrate

Taurine-conjugated bile acids are more water-soluble and less toxic than glyco-conjugated bile acids.

Bellentani S, et al. Taurine increases bile acid pool size and reduces bile saturation index in the hamster. J Lipid Research

1997;28:1021-1027.

Taurine scavenges free radicals

Taurine is able to attenuate DNA damage caused by aromatic amine compounds. Taurine is an antioxidant that specifically mediates the chloride ion and hypochlorous acid concentration, and protects the body from potentially toxic effects of aldehyde release.

Kozumbo WJ, Et al. Breakage and binding of DNA by reaction products of hypochlorous acid with aniline, l-naphthlamine or l-naphthol. Toxicol Appl

Pharmacol 1992;115:107-115.

Taurine protects against endotoxins

In experimental animals, taurine was found to significantly inhibit intestinal translocation and to protect the animals from endotoxaemic injury.

Wang WY. Intestinal endotoxin translocation in endotoxemic rats. Sheng Li Ko Hsueh Chin Chan 1995;26:41-44.

Glutathione

Oral glutathione increases tissue concentrations

“Thus, the results show that oral GSH can increase GSH concentrations in several tissues following GSH depletion, such as can occur in toxicological and pathological conditions in which GSH homeostasis is compromised. ”

• Aw, T. et. al.Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact 1991;80(1):89-97

Oral glutathione increases tissue concentrations

“Oral administration of GSH to these GSH-deficient animals gave statistically significant increases in GSH concentrations in kidney, heart, lung, brain, small intestine and skin but not in the liver ”

Aw, T. et. al.Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact 1991;80(1):89-97

Glutathione improves occupational chemical

exposure“When the endogenous GSH content was reduced by pretreatment of the cells with L-buthionine (S,R)-sulfoximine, the cytotoxicity of the herbicides increased strongly in both cell lines”Dierickx PJ. Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metolachlor, and propachlor in rat and human hepatoma-derived cultured cells. Cell Biol Toxicol. 1999; 15(5): 325-32.

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Glutathione improves occupational chemical

exposure“Different interactions with xenobiotic-metabolising phase I and II enzymes were observed, and GSH showed a protective effect against the acetanilides in both cell lines”

Dierickx PJ. Glutathione-dependent cytotoxicity of the chloroacetanilide herbicides alachlor, metolachlor, and

propachlor in rat and human hepatoma-derived cultured cells. Cell Biol Toxicol 1999;15(5):325-32

Glutathione Plays a Major Role in Heavy Metal

DetoxificationGlutathione has been shown to be a

significant factor in heavy metal mobilization and excretion, specifically with mercury, cadmium and arsenic.

Patrick L. Mercury Toxicity and antioxidants: Part 1: Role in glutathione and alpha lipoic acid in the treatment of mercury toxicity. Alt Med Rev 2002;7(6):456-471

Glutathione Plays a Major Role in Heavy Metal

DetoxificationGlutathione depletion and glutathione

supplementation have specific effects on mercury toxicity, both by altering antioxidant status in the body and by directly affecting excretion of mercury and heavy metals in the bile

Patrick L. Mercury Toxicity and antioxidants: Part 1: Role in glutathione and alpha lipoic acid in the treatment of mercury toxicity. Alt Med Rev 2002;7(6):456-471

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