islamic university gaza deanship of graduate studies biological sciences master program
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Islamic University Gaza Deanship of Graduate Studies Biological Sciences Master Program. Detoxification in Liver . Introduction. Humans are constantly exposed to exogenous and endogenous toxins. Detoxification is the process of transforming and removing toxins. Toxins Sources & Classes . - PowerPoint PPT PresentationTRANSCRIPT
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Islamic University GazaDeanship of Graduate Studies
Biological Sciences Master Program
Detoxification in Liver
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Introduction
• Humans are constantly exposed to exogenous and endogenous toxins.
• Detoxification is the process of transforming and removing toxins.
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Toxins Sources & Classes
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Liver• The liver is one of the four major organs
that eliminate toxins from the body. • The other three organs involved are the
kidneys, intestinal tract and skin.
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Liver • The liver plays a key role in most metabolic
processes, especially detoxification.
• The liver neutralizes a wide range of toxic chemicals, both those produced internally and those coming from the environment.
• The liver has to convert fat soluble toxins into water soluble substances that can be excreted from the body.
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Role of Liver in Detoxification
• Filtering the blood to remove large toxins,
• Synthesizes and secretes bile full of cholesterol and other fat-soluble toxins, and
• Enzymatic reactions to disassemble unwanted chemicals.
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Role of Liver in Detoxification
• This enzymatic process usually occurs in two steps referred to as phase I and phase II.
• Phase I directly neutralizes a toxin, or modifies the toxic chemical to form activated intermediates which are then neutralized by one of more of the several phase II enzyme systems.
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Filtering the Blood• Almost 2 quarts of blood pass through the liver
every minute for detoxification.
• Filtration of toxins is absolutely critical as the blood from the intestines contains high levels of bacteria, bacterial endotoxins, antigen-antibody complexes, and various other toxic substances.
• When working properly, the liver clears 99% of the bacteria and other toxins during the first pass.
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Bile Excretion• Each day the liver manufactures approximately 1
quart of bile, which serves as a carrier in which many toxic substances are dumped into the intestines.
• In the intestines, the bile and its toxic load are absorbed by fiber and excreted.
• However, a diet low in fiber results in inadequate
binding and reabsorption of the toxins.
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Liver Detoxification Pathways and Supportive Nutrients
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Phase I• Operates via Cytochrome P450 enzymes (Cyp)
• is a large and diverse group of enzymes that catalyze the oxidation of organic substances.
• Cytochromes P450 (CYPs) belong to the superfamily of proteins containing a heme cofactor and, therefore, are hemoproteins.
• The most cytochromes P450 is a monooxygenase reaction, e.g., insertion of one atom common reaction catalyzed by of oxygen into an organic substrate (RH) while the other oxygen atom is reduced to water:
RH + O2 + NADPH + H+ → ROH + H2O + NADP+
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Phase I• During this process free radicals are produced which,
if excessive, can damage the liver cells.
• Thus ensuring antioxidant status is important.
• The most important antioxidant for neutralizing the free radicals produced in phase I is glutathione.
• Glutathione (GSH) is oxidized to glutathione disulfide (GSSG).
• The liver and kidneys contain high levels of glutathione as they have the greatest exposure to toxins.
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Phase IAntioxidants
• An adequate supply of key antioxidants is therefore essential to prevent tissue damage.
• Reduced glutathione, • superoxide dismutase and • additional nutrients such as beta
carotene, vitamin E, selenium and N-acetyl-cysteine (NAC) will act as antioxidants.
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Phase I• If the phase II detoxification systems are not working
adequately, these intermediates can cause substantial damage, including the initiation of carcinogenic processes.
• The activity of the various cytochrome P450 enzymes varies significantly from one individual to another.
• The cytochrome P450s require several nutrients to function, such as copper, magnesium, zinc and vitamin C.
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Substances That Activate Phase I Detoxification
• Drugs: alcohol; nicotine in cigarette smoke; Phenobarbital; sulfonamides; steroids
• Foods: cabbage ملفوف, broccoli, and brussels sproutsكرنب ; charcoal-broiled meats; high-protein diet; oranges and tangerines يوسفي(but not grapefruits)
• Nutrients: niacin; vitamin B1; vitamin C
• Herbs: caraway and dill seeds
• Environmental toxins: carbon tetrachloride; exhaust fumes; paint fumes; dioxin; pesticides
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Substances That Inhibit Phase I Detoxification
• Drugs: benzodiazepines; antihistamines; cimetidine and other stomach-acid secretion blocking drugs; ketoconazole; sulfaphenazole
• Foods: naringenin from grapefruit juice; curcumin from turmeric; capsaicin form chili pepper; eugenol from clove oil; quercetin from onions
• Botanicals
• Other: aging; toxins from inappropriate bacteria in the intestines
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Phase II• Conjugation pathway.
• Because the liver cells add another substance such as cysteine, glycine, or a sulphur molecule to a toxic chemical to make it less harmful.
• As a result it makes the toxin water-soluble so that it may then be excreted from the body via watery fluids such as bile or urine.
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Phase IIThere are six
phase II detoxification pathways
–Glutathione conjugation–Amino acid conjugation–Methylation– Sulfation–Acetylation–Glucuronidation
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Phase II• The conjugation molecules are acted upon by specific
enzymes to catalyse the reaction step.
• Through conjugation, the liver is able to turn drugs, hormones and various toxins into excretable substances.
• For efficient phase two detoxification, the liver cells require sulphur-containing amino acids such as taurine and cysteine.
• The nutrients glycine, glutamine, choline and inositol are also required for efficient phase two detoxification.
• The antioxidant amino acid glutathione is also required for phase II detoxification.
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Glutathione and Sulfate Conjugate Formation
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Nutrients which activate Phase II • Aspartic acid• Blue green algae, Bee pollen• Cruciferous vegetables (broccoli, cabbage, brussels sprouts)• Glutamine, Glutamic acid and Glycine • Grapefruit juice contains naringenin, a substance which
slows down Phase 1 enzyme activity. This increases the half life of some drugs, causing them to remain active longer.
• Molybdenum• Sulfur-containing amino acids like Cysteine (or NAC), Taurine
or Methionine.• Sulfur-containing amino acid foods: meat protein, eggs• Sulphur-containing phytonutrients available from garlic,
onions, etc...• Vitamin B12
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Inhibitors of Phase II Detoxification Enzymes
• Glutathione conjugation: Selenium deficiency, vitamin B2 deficiency, glutathione deficiency, zinc deficiency
• Amino acid conjugation: Low protein diet
• Methylation: Folic acid or vitamin B12 deficiency
• Sulfation: Non-steroidal anti-inflammatory drugs (e.g. aspirin), tartrazine (yellow food dye), molybdenum deficiency
• Acetylation: Vitamin B2, B5, or C deficiency
• Glucuronidation: Aspirin
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Phase 1 & Phase 2 must be in balance• Another potential problem occurs because the toxins transformed
into activated intermediates by phase I are substantially more reactive. Unless quickly removed from the body by phase II detoxification mechanisms, they can cause widespread problems, especially carcinogenesis.
• Therefore, the rate at which phase I produces activated intermediates must be balanced by the rate at which phase II finishes their processing.
• If Phase I is more active than Phase II, a build up of reactive intermediate metabolites can occur which in turn can lead to tissue damage and disease. These people are referred to as "Pathological Detoxifiers".
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Toxic Overload• If the phase one and two detoxification pathways become overloaded,
there will be a build up of toxins in the body.
• Many of these toxins are fat soluble and incorporate themselves into fatty parts of the body where they may stay for years, if not for a lifetime.
• The brain and the endocrine (hormonal) glands are fatty organs, and are common sites for fat-soluble toxins to accumulate.
• This may result in symptoms of brain dysfunction and hormonal
imbalances, such as infertility, breast pain, menstrual disturbances, adrenal gland exhaustion and early menopause.
• Many of these chemicals (eg. pesticides, petrochemicals) are carcinogenic and have been implicated in the rising incidence of many cancers.
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Thank You Four Your Attention