review of laboratory and clinical studies of olestra, a
TRANSCRIPT
REVIEW
Review of laboratory and clinical studies of olestra,
a nonabsorbable lipid
CAR()! YN M HIRt,11()1/, Pl IL), RONAI.I) j J •\Nl)i\L 'I ls., r11n. Al •\N RR Tl ll)MSt)N, Mn, r11D
CM BERGHOLZ, RJ )ANDACEK, ABR THOMSON. Review of laboratory and clinical studies of olestra, a nonabsorbable lipid. Can J Gastroenterol 1991 ;5(4 ): 13 7-146. The classical unJerstamling offal digestion and absorption 1, proviJcJ as background for a review of researc h o n o lescra, a criglyceridedcnved lipid that 1s not <ligeMed or ahsorbcd from the 1mestinal lumen. Olescra (formerly 'sucrose polyester') is the generic name proposed for the mixture of the hcxa, hepta and ocra long c hain fatty acid esters of sucrose. O lcst ra has the physical properues of fat and can therefore function as a zero caloric fat replacement in 100Js. The fate and effects of o lesrrn in che gastrointestinal tract have hccn extensively investigated 111 animals and humans. Evidence from a variety n( studies shows tht1t o lestra is not digested o r ahsorbed and b not meraholi:cJ hy colonit. microffora. Feeding studies in five different species of animab show that olestra is nontox ic and noncarc inogenic, and c:n1se:; no morpho l\igical changes 111 any ti ssues of the g;1strointescinal trnct. Comumptio n of o lestrn fotxls does not alter gastril emptying, transit through the small and large howd, hile mJ physiology, howcl function, or focal pl-! , water and elec trolytes. Nutritinnal rc,earch shows no effect nn absorptio n of macronutnencs. Highly l1pophil1c matcnab such as cholesterol a nd vitnmin E have the potential to partition in to ,ibtra, thereby dec reas ing their soluhilization in intestmal micelles and sub,cquent absorption. C linical research shows a modest reductio n in scrum ddcsterol and vitamin E levels. The effect o n vitamin E absorption can be o ffact hy supplementation of olestra with vitamin E. The ~rntus of v1tam1m D ,ind K anJ ahsorpt ion of I ipophilic drugs arc not altered by daily consumption of 18 g ,ibtra. Alt hough scrum rctino l leve ls arc not reduceJ, add1ttona l research is focusing on effects of olestra on hepatic stores of v1c.im111 A to assess the appropriateness of supplemental ion. Using olcstra to reduce the amount of fat 111
high fat fonds, without affect ingothcr nutrienb, should contrihutc tn cl diet lower m energy fro m fat a nd higher in energy from carbohydrate. ( Pour resume, vmr (l<lJ!~ 138)
Key Words: Far suhscituce, Ncmahsorbahle li/iid. Olestra
D1visum of ( J(lltrocntcrnlo!f,, l lu1wrn1y oj Alhcrw, Etlnwmon, /\lll<!rta. and l'rut!t'r & !,~mhle C 'omf>clll'/, ( '.mnmuu, , ( lh10, L'SA
Corre1/>mulcncr ancl rcfmnc., I )1 Kl) Lam1on, Thl' l'nu:ier & t iamhle ( :wnf>llll'I , W1111on 1/1/1 Technical Ccma. 607 / Cemrr / 1,// /focul. Cmcmrwu. 011 4'i224 . l 1<;,\ Trle[lhonc ('i 13) 634-6700
Rcwwcl for f>uhl1rauon Ma:, 3, / 99 I Atw(>tcd June 11. 1991
T l II.RI· I IA\ E Hf EN NU1'1l'R0U's -.;LJ( -
c inu and sLholarl y rl·vicws puhlishcd recently o n lipid ahsnrpl inn (1 -9). It was over 15 years ago th.it DietsLhy of Dallas, Texas ( I 0- 12) for
mulmcd the now ch1ssical, simple and log1Lal approach w understanding the steps 111\'olved 111 lipid d1ge!)tion and ahsnrpt ion , including the role of the pancreas m the secretion of lipascs, the role of the liver 111 the secret 11m llf hdc acids needed for mi cellar soluhil ization ,
,md rhc mlc of the t.'n te rocytcs of the Jl'Junal mucosa 111 the uprnke, cstcn fi cmion and synthesis o( I ipoprotc im 111 -
cnrporatcd into Lhylom1uons (Figure I).
Chylomicrom cross the hawlatl·rnl mcmhrane of the cntcrocytc and enter
liN the I~ mphat1cs and then the b loodstream. As a result of tlw hydro lys1, of
dietary lip ids, mixed micelles an: formed with h1k salts, soluhil1:111g the l1pnlyt1L products and delivering fatly ,1uds, monogly< cndcs, l holesll'r11I. phosphol1p1ds .md other l1pophilcs tn the aq11cous 1111 c rfocc at l he hrw,h h11rder membrane (BRM). Nutrients may
L ross rhe BRM through po re,, 1a ctrrtl'r med1auon (with or wtthout L'nergy ex
penditure), through the hu lk l1p1d phase, or hetween cclk The dassiGtl cons1dcration 1s ,me 111 which l1 p1d uptake occur, hy passive diffusion th rough the intcstmal RRM. Hmwvcr, heforc
l1polyt IL pnxlu<.:t, can traverse the
Rrnu, ,nu e111/
Tour d'horizon des etudes cliniques et de laboratoire portant sur l'olestra - Lipide non assimilable
RESUME: La comprehension classique <lu mccanismc de digestion et d'absorpt ion <les graisses fournir le cadre de ce rour d'horizon de la recherchc consacree a l'olestra, un lipi<le derive <les t riglycerides qui n'est ni digere ni absorbe <lans la lumiere intestinale. L'olcstra, ancienncment appele "sucrose polyester", est le nom generique qui designe le melange d'acicles gras a cha7ne tongue/esters de sucrose. L'olestra a les caracteristiqucs physiques des graisses et peut clone servir de substituL alimentaire exempt de calorie. Le sort et les effecs de l'olestra dans lcs voics digestives ont fair l'objet d'etu<les exhaustives chez !'animal ct l'etrc humain. Les rcsu trats provcnant de divers essais demontrentque l'olestra n'est ni <ligere ni absorhe ct qu'il n'est pas metabol ise par la microflorc colique. Des etudes portant sur !'administration du produit chez cinq cspeces animates Jifferentes montrent quc l'olestra n'est ni toxique ni carcinogcne et qu'it n'entra7ne aucun changement morphologique au niveau des tissus de l'appareil gascro-intestinal. La consommation d'aliments a base d'olest ra nc mo<lifie ni la vidange gastriquc, ni le transit au nivcau du grcle ou du gros intestin, ni les caracreres physiologique~ des acides bil iaires, n i la fonction intest inale, ni le pH , la teneur en eau ou l'ionogramme des matieres fecales. La recherche en nutrition ne rcvele aucun effet sur ['absorption de:; macronutriments. Les produ its fortement lipophilcs tels que le cholesterol et la vitamine E peuvent se scinder <lans l'olcstra, ce qui reduit !cur solubilite dans lcs micelles intestinales et leur absorption subsequentc. La recherche cl iniquc montre une fa ible reduction de la cholcsterolemie er des taux scriques de vitamine E. Les effets sur !'absorption de la vi tam inc E peuvent errc corrige~ par un apport complementaire de vitamine E. La presence des vitamines D et K, ct !'absorption des med icaments lipophiles, n'est pas perturbee par la consommarion quotidienne <le 18 g d'olestra. Bien que les taux seriques de rcrinol ne soient pas reduits, des essais supplementaires erudient les effets de l'o testra sur les reserves hcpatiques de vitamine A afin J'cvaluer le bien -fonde d'un apport complementaire eventuel. L'utilisation de l'olesrra permet Jc reduirc la tencur en graisses des aliments hyperlipidiques sans affecter les autres nutriments; clle <levraic contrihucr a rcdui re l'apport energctiquc d'origine lipidique et a augmenter l'energie provenant J es hydrates <le carhone.
memhrane, the lipid; must fi rst pass through the unstirred water layer.
The unstm ed water layer represents a series nf l;imellae of poorly stirred water through which nutrients must
PANCREAS • LIP AS ES
Hydrolys is NEUTRAL Emuls ifica tion
FAT FA .. MG
.. LUM EN
pass from the bulk phase across the BBM. Its resistance is determined by the thickness and surface area of the umtirrcd water layer, as well as by the d iffusion coefficient of the nutrient.
LIVER • BILE ACIDS Uptake
Es terification Micelle Lipoprotein
Form::ition Synthesis
Mixed Micelle .. Chylomicron .. LUl\iEN ENTEROCYTE
Figure I ) /.og1rnl a/i/iroac/1 to 1mdernanding ilte steps mmlved 111 Ii/lid dr[!e.,wm and alm1r/1t 11m
The net effect of the unst irre<l water layer is to reduce the concentration of solute between the higher values seen in the intestinal lumen and the lower values seen at the aqueous-BBM interface. T his latter concentration is the value 'seen' by the membrane and its carriers. Estimates of thickness of the unstirred water layer vary depending on site and experimental preparation. For example, the thickness of the unstirreJ water layer in the dog intestine is approximately 500 µm, a large value compared with the height of the villus (200 to 500 µm), the glycoca lyx (0.1 to 0.5 µm), the height of the micmvillus (I µm) or the thickness of the BBM itself (O.l µm). The thickness of the unstirred water layer may vary along the length of the villus, as wil l its surface area. For example, the thickness and surface area of the unsti rred water layer may be lower in the upper versus the lower portions of the villus. When the bulk phase in the intestinal lumen 1s
stirred, the thickness of the unstirred water layer falb, its surface area will rise, and the net effect is a fall in unstirred water layer resistance . However, even with vigorous stirring the effective surface area of the unst irred layer is much less than che surface area of the villi or the microvilli .
The functional surface area of the microvill us membrane is another factor in nutrient absorption. For example, for amino acids, glucose and certain lipids, most uptake occurs in the upper onethird of the vi llus. It would also appe~r that the villus tip is more acidic than
Chylomicrons .. LYMPHATICS BLOOD
138 CAN J (,A<;Tflt11-NTIR()I Vo, 5 Nn 4 )lll Y/AUt,UST 1991
TRIGLYCERIDE (Glycerol with Fatty Acids)
OR
A OR OR
RO
OLESTRA (Sucrose with 6 • 8 Fatty Acids)
OR
OR
RO RO
Figure 2) Comparison of rhe srrncwre of a triglycencle molecule wHh char of ole.ma. 0 Oxygen
2,200 1 2.100
...J
E C: E ~ u.. 200 u.. V) Q)
160
0 ~ ::I.
100
54
I 9 05 0
Me1ha11ol Elhylene Glycerol Erylhnlol Adoni101 Sorb,101 Sucrose (I) Glycol (2) (3) Hl (5) (6) (8)
Alcohol Moiety (Number of Fatty Acid Esters)
Figure 3) Re/a rive raws of hydrolysis of che complete okace esters of a series of polyol mo1ecie.1 mcubated ar 27"C with fl11idfrom the rat common hile-/>ancrearic duct and maintam<!d at pH 9. Th~ rare of hydwlys1s 1s repont!d Cll µmo/ free fatr;1 acid ( FFA) released per min per mL of ~n~:ml<' preparation
the vi llus base. Fnr fart y acids, protonation reduces their solubility in micelles but also inc reases their preferential partitioning into the BBM.
Lipids solubili:ed in micelles J o nm enter the cnterocytes wi th intact micelles; instead , there i~ evidence that lipid absorption occurs predominantly through partitioning from the micellc into an obligatory aqueous phase and then across the BBM. Under experimental condition~ some uptake may occur d irectly from micelles into the BBM. It has a lso recently been suggested that there may be a distinc t microvillus membrane fa tty ac id binding protein whic h might be respon sible
for ve ry early uptake of long c hain fatty acids anJ cholesterol. Thts is suggested by studies showing thm a t ve ry low concentrations of lipid, there is a curvi linear relationship between substrate concentration anJ uptake. Although there are many poss ible explanatio ns for this no nlinear re lationship, there is other evidence that uptake of one fatty acid may be inhibited by the presence nf a second faery ac id , by changes in unst irred water layer resistance or pH, or by remova l ot sndium.
Res istance of the unstirred water layer also varies in health anJ disease, represent ing one of several mecl,anisms by which the intestine can
CAN J G1\STROENTERl )L Vl )( 5 No 4 JULY/ Aurn.;sT 1991
Review of studies of oleslra
adapt nutrient transport. There i, no Joubt thm the intestme 1, capable of adaptation, wnh incre,1,e, llr decreases in the uptake of lipids as well as other nutrients. T hb adapt1vc process may involvc alteration, in transport rare, Mic haelis constant, or permeability and/or morphology of the intestine. This adaptation can normake l1p1d uptake anJ thus benefit the ind1viJual.
Lct us now consider a majl)r, JXltentially important innovat ion in nu trition, t he development of o lest ra , a nonahsurhahle lipid that could he used to replace fat in a wrde variety of fot,Js.
BACKGROUND O lestra is the generic name t,1r the
mixture of hexa-, hept.1- ,md t1cr,1-este rs ohucrose formed with ltmg cha111 fatty acids bolmed from ,Tgetahlc llil. It i~ the subset of sucrose polyesters which is nm hydroly:ed by panLreatic lipase and is then.Jore m1t ahsorhed. A, shown in Figure 2, ole,tra ha, a ,ucm,c core 111 place of the glycerol core nf triglyceride and is estcrified with six to eigh t fauy acids rather than thn:c. Steric hindrance due l\l the larger bulk of the nlcstrn molecule appnrenrly a<.:
counts for the lack of hydrolysis hy lipases. In contra~L Lu the higher e,rers, the mono-, di- and tr iesters of ,ucwse are fully digested and absorhcd and arc used in f<xids as emuls1f1ers anJ to coat fruit.
The disrnvery of nlestra resulted from resemch on lipid digeslinn and absorption. FH Mamon anJ RA Volpenhcin at Procter & Gamble ( l 3) synthe 1zed a series of polyols fu lly este nficd with nne to eigh t oleic acids, and invest igated the rate of hydrolysis of each by pancreatic lipolytic enzymes in vitro. As shown in Figure 3, when a mixture of rat pancreatic nnJ bile fluid was added to escerified polyob, there was a sharp decrease in the race of hydrolys is of pol yob having more than three fatty acid esters. No mea,urahle hydrolysis was observed for sorhirol esterified with six fatty acids or sucrose este rifieJ with eight fatty acids. Fat balance and absorption stud ies in thoracic duct-cannulated rats showed char sucrose ocra-oleate was not absorbed ( 14.15 ), prov iding convi ncing
139
ev idence that h yd ro lysis o f lipids 1s a pn:: rcqu1s ite for absorpl io n .
T cchnically, o lcstra can be used 111-
terchangeably with fo1 in a wide va ri ety
,)f' foods (1 6). Because i1 s physical
properties arc simi lar w those of conventional rriglyccridcs, It can he
hlended with con venuo nal fots and used in coo king, haking or deep frying.
Foods made with olesrrn have the same taste and 1ex tu rc as those made with
full calorie fats. S imilarly, the hearing and storage stahili t ics a rc comparable to those of con ventio nal far.
P rocter & U amhlc has filed a 'Food Additive Pe tit ion' with t he US food and Drug A dministrat io n (FDA ) ,md a 'Food Addit ive Suhmiss ion' with the
C anadian I lc,1lrh Protectilm Branch requesting approval to use o lcstrn tn
replace 100% of the o il used in preparing savory snac ks such as corn and potato chips . Additiona l uses will require new petitions to he fi led and app roved.
The suhmissi(m s inc lude rep,in, of o ver J 00 lab(JJ'at(JJ'y a nd a nimal srud ies and conrrn ll ed c lin ica l i1west1garions
involving thousnnds lif subjec ts. Results nr ex tensive research o n absorptio n , c h ron ic 1oxic ity, c.irc inogenicit y, reproJuc ti,m , n utrit inn , and gast rnin test inal physio logy suppo rt the
safe ty of olcst rn in foods ( l 7-21). Because o lesrrn is nor J 1gestl'd and nllt ahsorheJ, the gastroin tes1 in:i l tract i;, the only , ll'gan system e xposed to o lcsw1.
L1pophilic mate ri als can partit iun 111to this unahsnrhed lip id; thus n lest ra has the potentia l w decre,lSl' 1he ah;,orpt ion o f lipliphdic mn lccu le;, hy
compe ting with the m ixed micelles f<ir rhem (24) .
A review ,if the research perta ining to the fore and effec ts o f o lestra 111 the
gastrninresri n,11 trnc t wil l provide a n
o w rv il'W o f the bio logical rmre rties o f o lcstra. T he results of th is researc h provide evide nce that o lcst ra 1s 1101 ahsorhed m mc taho l i:cd in the gasrw
intest in.11 trac t and dl1c~ not affec t ga;.tmintesti na l mo rph ulogy, gast ric emptying, panc remic respo nse, b ile ac id physio logy or howcl functiun .
These Jara are re\' iewed alo ng with st udies on the potcmial fo r o lesrrn to
140
TABLE 1 Olestra long term animal studies
Reference Species Duration % (w /w) of diet
20 Rat 24 months o. 1. 5. 9 20 Rat 24 months 0.9 23 Dog 20months o. 5. 10 22 Monkey 44 months 0.8
affect ,:bsorpt ion of nutnenrs and organ ic wx icants.
OLESTRA ABSORPTION AND METABOLISM
The lack of ahsnrpt io n of o lestra is
an impo rtanr considera tion in the assessme nt o f the !:>afcty o f o leHrn nnd its effects o n t he gast roint est inal t mer. Recause o lestra is not h yd rolyzed, it docs not form mixed micelles with hile salts
and is therefore not transported to the BBM of the cnrerocytcs where faery
ac ids a nd mo noglyceridcs a re absorbed . It is excreted unchanged in the feces, ind icating I hat it is no t meta ho I ized hy micrnnrganism s in the colo n ( 17).
E\'1dcnce that ,ilest ra is not metaholized or nhwrhed comes fmm a n imal st udies wi th rndiolabelled olestra, fat balance studies in anima b a nd hum<1ns,
a nd analys is of t issue~ from mo n keys a nd rats in long te rm feeding studies ( 14, 17, 19). S ince obtra b ll()t ahsnrheJ , it was necessary t() use intra
venous inject ion nf rnd iolahc lled o lestrn tn de t('rm ine which organs wo uld take up o lcstra and whet her it
wuuld be me tabo lized if 1t were absorhcd. T he results showed that int ravenously nd m i111stered ()lcM ra was
rnr id ly t t1ken up primaril y by the live r nm! 1hen excreted slnwly, in tact , into the hilc wn h a half-life nl ahout fi ve days ( l 9; RJ .J anJ acek , Procte r & Camble, unpuhlished data) . O btrn
entered the intestinal lumen in b ile and was excre ted unc ha nged fro m the hody.
W hen scns111 vc c h romatographic
methods were used to a nalyze livcr t issue from rats fed o lcstra for two years or mo n keys fed u lestra f,,r 29 monrhs, no
nlestra was derccrcd , ind icat ing tha t it dl1es nm accumulate in t issues ( 19 ) . The ch romatogra ph ic me rhods would have d e tec ted LO 'i tn 10 6lX, of rhc
tota l a mo unt of olestrn consumed by I . I R d· . 14c t 1e anuna s. eccnt stu 1es usmg -
la be lled nlestrn a lso showcJ J ctecu nn o f raJ iu labcl 111 li p id ex trnct, of liver
from ra ts only near the limi ts of detect ion of approx imatel y 4x1 0 4% nl 1hl· ad ministe red dose (KW M ille r, Procter & C amble, unpublished d ,i ra ).
MORPHOLOGICAL EVALUATION OF THE
GASTROINTESTINAL TRACT Tissues of the gast roin 1est inal t ract
taken from ;1111mab in shon and long term feeding studies (Tahle l ) were ex
amined grossly and micmscnpically. In these studies il1L're was no evidence that ob,trn caused any adverse effect Jetectahle by c linic.i i measures or hi,
topatho logy. Specia l lipid stnmmg techniques used in a 9 1 d.1y sl udy with nlls showed no ,iccumulat io n of fat 111 th t' intestinal wall. In addi1 io n , no trcai men t-re latcd cffc<..t~ were oh,crvcJ
in Pcyer's pa1 chcs llf rat s after t wo year~ (20). A naly~ i, of mest•n teric lymph
nndes l1f mon keys fed o lestra at 8% (w/w) of the d iet fnr 29 mo n ths showed no ,iccumula t 1<111 o f n lestra ( 19).
BOWEL FUNCTION A number of feca l paramete r~ and
m hcr indicatms of n nrmal hmvel func
rion were evaluated in an imal and c linical invest igauons. !-=ei.:,d I 1p1d
(other than olcs1 r,1), wat er, t•lcctrol yte, and pH \\ere 110 1 a ffec ted hy nle~trn. Frequency o f bowe l movement wa,
no rmal, even aftcr cnn~umpt inn uf 50 g/J ay obt ra ( L8) . Scat te red inc idence,
of ,ofter ,mob havc hce n uhservcd in an ima l (24 ) and h uman Mud1cs ( 17) wnh o lest ra . T he soft stools re~uli from the lmgc amount o f un;dte red olest ra
excre ted in the feces and do no t repn.:scn1 a phy,1lllogic tl respnnsc 10 n les trn . Dia rrhe;i w,b n,ll ,1h~ervetl. Some ;.uh
Jects who h ,1d prnhlems wi th const ipa-
11u n considered th is effect a hencfi1 ( 17 ).
I ligh lewis of li4u1J olcst ra uscJ in '<lme of the early stuJies produced ,ponrnncous leakage of oi l drops from
the gastromte,-cinal I met. This problem w,,s corrected hy increasmg clw vbcosity and melung poant nt lllcstra to
preclude oil phase separation frnm fecal ,ol1ds at body temperature. S<.:attered .ind transitory incidences nf common c,1-rro1ntestinal symptom~ su<.:h as flatulence, hloaring ,mJ heartburn reported in early clinical studies, were :,"ociated with high doses (50 to
greater than I 00 g) of l1qu1d lllestrn 111
tormula di<.'ts. Cont rolled clinical ,tudics with reformulated ,ilestra in-1olvmg over 2000 suhieus, horh adults ,ind children. showed n,1 oil loss anJ no ,tatbtically significant Jiffcrence in ,uhiecti\'C I y evaluated ga~troa n test mal ,ymproms following single or multiple J,,y consumpu,m of foods m,1de with the higher melting olestra formularinns vcr.;us triglycenJe placeho contrnls.
GASTRIC EMPTYING AND GASTROINTESTINAL
TRANSIT TIME The effou of llkstra un gastrtL
emptying was mvcsllgateJ 111 cl111 1cal tri,ils conducted b'r C,,rt1ll ct al (25,26). In the first clmical 1mestigat1on, 14C-lahclleJ olesrra was validated ,,,a nonabsorhable mmker for the lipid rhase. In a second study, nlestra was 1N'J as a nonhyJrolyzahle l1p1J tn stuJy the mechanism of gastric emptying of the l1p1d phase. In addition Ill d1L' r,1d1olnhclb.l olestra UM:d as a marker, .a t1ital of 20 g ulcst ra was adm inistered r1,1 1ntraga,tr1L t uhe at four mrervals Jurmg eating of a meal containing 4.7 g fa t. D1ge~ted sample, were collected thniugh an 111Jwel11ng mullllumcn duodenal tuhe ,ll IO mm 1111crval~. Most ol th<: ulest ra was cmprieJ Ill the first 2 h ,along with thL· ".ucr. Solid, ,111J fot wen.· emr11eJ over ,, pcmxl of 6 h as prL·v1m1sly rL·p1Jrtcd (26), uggcsung that ulestra J1J not Jday itl> own empt ymg and did not mterfcrc with re~ponse to sign,ib from the proJucts nf for digestion.
The dtect of olestra on g.1s1 ro1ntes-11n,1l tranl>lt was alsu measured in 30 healthy subjccb usmg gamma scint 1-gr.1phy ( unpublished Jam). Olcl>tra
Review of studies of otestro
-0 Q) - 100 (..) Q)
0 90
0 80 Q) t6 ?) Cf) 70 0 0 60
<{ 50 0
0 40 0
30 ---0 20 '<f ..___.
10 ...... 0
0 ~ 1 5 2 5 0
2 5 15 3 5 4 5 5 s 21 5
~ Con1rol Hours After Intubation
t Oloslra
Figure 4) C:1111111/mit•c {,! rcc11taj?c? renn•en in /irk· of 14C .d1enodeo\ydwl1c and (C{)CA) ml• mumcaed w nu, /,.._ mwh<w1111 followl'd 1-.v ,o,l,,·1111 oil or C:.0/C:.O ,o'l/lll'ml ml/ol<!,ITll Numl'll'r, Ill fl<1n:111hc,c•, an.' , c,md.anl ,·n·11r m.:mtirc·mcn1.,
( 7. 5, 15 or 30 g) indudeJ in ,l smglc, 1s11c;1lom: and 1solipid meal (hrL·akf.t,t) h,1J mi s1gnif'icant effect on gastric L'mp1 \ mg, sm,111 howcl tr,ms1t or large hmvcl transit, rch1t1ve to high and low fat tn1 . .dyccndL· control meals.
Olt•,trn h.is ,1bo heen shuwn nut 111 stimulate a panuealll rL·sponse 111 nits ( 2 7). T1,sUL' kveb nf pane reat ll en:'ynll.:s 111 rah kd 11kstra ,ll 5'~n (w/w) ,11 thL· d1e1 or 16''i, m n1mh111,1t111n with 4% hydmgenatL·J palm nil for 28 days, resemhled rh, Isl' 111 rats L',lt 111~ ,t lnw faa d iet.
RL·sults oft 11l'se stud IL'' 111JicalL' I hat ,1lt•stra 1s n,ll pL'rLelVL'J .1, a d1gest1hle fat hy the gastnuntL·stmal tn1lt ,md docs 111 ll interfere w11 h tl1L· gener,1t ion of. ur rL·spon,L' to, s1gn.1ls from nther 01mponL·nr, of l he diet
BILE ACIDS A number of ,1 ud1e, were conducted
to investigate the potL'nllal dfrcts of nlesrra on h1k .,ud rhys1nlogy (24.28-H). These ,tud1es 111LluJL·d quanlltauve ,111d quali1.1t1vc evaluation of bile ac id ahsorpuon and synrhe»1s, .md hil,ary anJ fcLal h1k ,1ud profiles.
In a study that assessed bile auJ absorpt1(H) directly, bale Juct-cannu lmed rah \\•erL' adrn1111stercd 14c>1..hen0Je-
u,ychol1L acid (l ' LX:A) by 1nruha11on, follmwd hy soyhl'an oil in one group .111d 50/50 wyhean ml/olestra 111 annther grout (22) . hgure 4 show, the u1mulat 1ve 1 ( ' nu 1vity 111 tlw hile culll'cted at mtcrvab uver 21 . 5 h alter intuhauon . Adm1111,trat1on of ole,trn with ( ' L)CA had 1111 effect nn tlw rate nr amount of rad,olahel ahso1 hcd. These results suggest th,ll ahs11rpuon nl umJugated hik ,,c1tls, I hl' more commun species 111 tl1L' ante,tine, wou ld not hl· ,1fkul'd h\ ok,1 ra, sancl' Cl)CA 1s one of the mmt l1pophd1L hale auds, .111d h1k ,Kid, conJug,HL·J w1rh glycine , 1r taunnL' are morL' polar.
Rile ,H.:1J synthesis and fecal cxuet 1011 wa, exam med in a l 4 Jay study in wh1Lh rats \verL' fed soybean oi l, l1qu1J u lestra ,It 8% ( w/w) of the J1et, or sol id ulcstra at WX, (w/w) of the diet ,ilong Wit h 21\i hardened ralm rnl 111 all groups ( 2 4). On day 8, \ >chok,ternl was admmi,tered mtrnvenously and feces were colleucJ d,1ily for thL· next SL'Ven Jays. hgurc 5 shows thL· u1mulat 1ve excretion of 1\ : in the ncutrnl and acidll steroid fractions. There was no effect uf either olestrn ,ample ,m the rate or tmal percenrage nf lahclbl fecal hale .1c1ds excreted (24). Olcstrn enh,mLeJ t·xcrctaon of neutral steroads, ,,s pre-
141
RERGI lt11/ ec a/
20.0
h~l }eu, Acids
18.0
16.0 ~,i:,giJ 14.0
4Bil Cl) en 12.0 0
~I 0 'O Cl) 10.0 {JJ' u Cl)
·2
~ 8.0 /1 } "'"'"' Stedods
0
6.0
§ 4.0
I t:,. Liquid Olestra D Solid Olestra
20 O Soybean Oil
2 3 4 5 6 7 Day of Fecal Collection
Figure 5) C1m111lauw c:xcrecion of 14c: rn che newral and acidic fecal qeroid fracriom in rncs adm11111cered 14C-clwlc1terol m[rawnrn15/y on da'I Ii of a 1-1 c.hv .rnui'I 111 wh,c/1 rm.1 wen: fed scnhean "tl, l1qwd ole.ma or solid oles cm each hlended 80/ 20 w,rh hardened /)aim ml. The olema or soybean ml concenrrauon was 8% ( w/w) of the diet. Swoi.l u•er<' collc:cced on da,•.1 I ro 7 />mt in1ection of radwlahellcd chob Cc.'rol
TABLE 2 Fecal bile acid excretion of rats fed olestra at 5% (w / w) of the diet for two months
Bile acid Uthocholic 3b. 12-alpha-dihydroxycholanolc Deoxycholic 3a. 12-beta-dihydroxycholanoic ChenodeoxychoHc Ursodeoxycholic Cholic Beta-murichollc Others Total
G roups
Control (mg/ day) Olestra (mg/ day) 0.4±0.08 0.4±0.07 0.1±0.01 0.2±0.05 32±0.6 2.5±0.3
0.04±0.01 0.02±0.002 10.4±1.2 11.9±1.5
1.9±0.6 l 6±0.2 0.4±0.06 0.6±0.09 1.5±0.4 1 8±03 0.7±0.09 09±0.l
18.6 19.9 Values given ore mean± standard dev1ot1on for n=S
viously demonst rated u~ing other methods (28,29). In ,mother study in which rnts were fed olcst ra at 0% or 5% of the diet for two years, feces were collected for bi le ;iciJ analysis over a 24 h period at one, two and 24 month~ of
142
rhe ~tudy. Repre~enrntive da ta ,ire shown in Tahlc 2. No ~ignificant differcncr wa~ seen in the hile acid profile or rhe total amount excreted.
In a human ~tudy, 24 normal healthy male suhject, were fed ulest ra in-
creasing from O tn 40 g/day fnr four 10-day periods ( 30). Fecal samples were collected for five Jays at e,1ch Jose. Analysis of fecal bile acid~ ~howed widt variahi liry among subject~ at baseline. With nlestra, there was no significant difference in amounr.s nf bile acids excreted, no Jose rc~ponse, and no consistent effect nn hile acid composition. One subject showed a decrease 111 secondary bile acids, hut the decrease showed no Jose response with respect to nlcstra. In two ocher studies, increases in bile acid excretion were reported for wme subjects ( 1 l, E). In these studies nlestra intake was very high (50 to 90 g/day in liquid formula hypocaloric diets).
Bile was also collected from nus foJ 5% olest ra in the diet for fi ve and lO weeks. There was no difference 111 bil iary bile ..1cid profiles in nlestra-fcJ and chow-fed ani mals. Rile was also sampled seven times over the course of one ycnr in a study in which Afr ican green monkeys were fed olcst ra at 6% of the d iet. Analysis of hile showed no effect on hi le ac,J profil..:, pool si:c, hilc composition or lithogcnicity mdcx relative to an imals fed the hasal dit:t. Crouse and Crundy (3 1} also reported that saturation of gallhladder hilc in
man was not adversely affected by ingestion of olestra 50 g/day for six wecb. I( hilc ac id ahsorption were decrea\cd by obtra, the hiliary hilc acid profile would show an mcreasc in the propnruon nf primnry hile acids Jue to an increase in ,ynthesis hy the liver.
COLONIC MICROFLORA fecal rl'Cnvcry nf \1lcMra from
animab in long cerm foed ing studies and from humans in clinical investigations indicates thm \llestrn is noc mctahol1zcJ hy colonic microflnra. In vitr\1 expcrimcms also demonst rated th,1r rad iolabel led oles[ rn was not mctaholized by fecal microf1nra cnllcucJ anacrohic.illy from seven ~uhjects wlm had consumed nlcsrra for 30 days ( 3 3) Measurement of volat ilc fa t ty acllil. lactic ac id, and hydrogen and methan, product inn in or her in vitro exprnmems showed ! hm olest r;1 d id not af feet microhial fermcntatiun.
As J1,cusscd .1hovc, olcstra d id nnt
affect fecal or biliary bile aciJ profile~. mc.licating no effect on microbial Jeconjugation anJ hiotransformc1tion of primary to ~cconJary bile aciJs. At higher intakes a Jecrcasc 111 hioavailability of neutral sterol sub~trate Jue to partitioning into o lestra Jecreascs bioconvcrsion by 0.6°/o/g olcstra among individuals with a microflora that metabolizes these substrates (29). Studies in animals and humans have also shown no effect of olestra on fecal nitrogen excretion, providing evidence that olestra does not affect microbial biomass. S ince gut microflora play a critical role in colonic physiology, the lack of an effect of olcstra on fecal water, electrolytes and pH provide aJditional ev idence that olestra Joes not affect the colonic microflma.
CHOLESTEROL ABSORPTION The absorption of cholesterol is
decreascJ when olestra is included in the diet. This effect has hecn observed when the source of mtestinal cholc,terol is either exogci:w us (dietary) or endogenous (biliary or intcstmal cell). The effect of obtrn 14 g/day on cholesterol .1bsorption was recently investigated in a crossover study among 20 healthy subjects who mgested ra<liolabclled chobterol in butrer and nlestra-containing spread (34). During theolcstra regimen, cholesterol absmprion was 46.7±1.6% compared with 58. l± l. l % during the r~riod of butter consumption. T he difference was .1tatistically significant.
A mentioned above and shown in Figure 5, olcstra enhanced the excretion of neutral sterniJ~ in nus injected with 14C-lahellcd cholesterol (24). Since the animals in that study received a cholc~terol-free Jict, Lhc ohserved increase in neutral steroid excretion reflected an effect of o lc~tra on the re-abwrption of choleMcrol from an endogenous source, presumably originating in bi le or mtcsrinal cells.
The decrease in c1hsorption of dietarv choleste rol in the presence of olestra results from partitioning of cholesterol in foods inrn the olestra phase in the gastrointest inal trnct, which retains a portion and carries it from the body. The effect on cndo-
gcnous cho lesterol must, al least in part, involve the exchange of cholesterol frurn the aqueous system of bile tnto the olestra o il phase.
MACRO NUTRIENT ABSORPTION
Since the primary function of the gastrointestinal system is the digestion and absorption of macro- and m1cronutrients, the potential for olestra interference with this function is an imrortant area of investigation. Looking fi rst at macronutrients, numerous stud ies in animab and humans have demonstrated char olestra does nm affect the absorption of proteins, carbohydrates or fars (20,2 l ,2 3 ). Indirect evidence comes from results of long term feeding stud ies in rats (20) anJ Jogs (23) anJ Jata from rwo generation reproduction study in rats (21 ). None of these stud ies showed any effect of olcstra on the growth, dcvclnpment or longevity of the animals nnr any clinical indicator of health Matus. Studies have also been conducted specifically to assess the potential of olcstra w affect ahsorpt ion of each macronutrient.
In a ~tudy of absorption of nral glucose in rats, olestra did not affect the time en peak blood glucose concentration, the peak blood glucose cnncentration, or the area under the concentration-versus-rime curve. Olestrn ha~ abo been shown not lll affect fastmg hlnod sugar concentrations 111 rats, Jogs and humans, further demonstrating that it docs nor inte1+ere with carbnhydratc absorption. For example, fasting blood glucose levels in patients with adult onset diabetes were unaffected by the ingestinn of olestra 90 g/day for up to 50 days 02), providing evidence that carbohydrate absorption is unaffected by olcstrn.
Evidence that absorption oi protetns and amino acids is unaffected by olestra comes from a variety of studies. Olcstra, tested at up to 15% of diet by weight, had no effect on ni trogen balance measured in 28-Jay dog and 91-day rat feeding studies (FH Mauson, EJ Hollenbach, Procter & Gamble, personal communication). In a study of rats dosed with radiolabellcd methionine o r phenylalanine in water fo llowed by
CAN J GASTROENnROL VOL 5 No 4 JULY/Aut;usT 1991
Review of studies of olestro
olestra or corn oil, there was no difference in chc rate of recovery of 14C in carbon d ioxide, urine l)r feces (WB Gihson, Procter & Gamble, personal communication). Since amino acids arc not stored hy the hody and thus total body pools arc smal l, differences in the rate of absorption will be readily reflected hy differences in carabolic rates.
The similarity of radiolabe lled carbon diox ide expiration with time het ween o lestra-feJ and control animab inJicates tha t olestra did not affect either the rate of ahsorpuon or the overall disposition of amino acids. Measurement of fecal nitrogen m a human clinical ,Ludy showed a mean excretion of l .42±0.38 g per 24 h during a LO-Jay hasal reriod and 1.37±0.27 g per 24 h with 50 g/Jay olestra in the diet (CJ Glueck, RW Fallat, University of Cincinatti, personal communication), providing further evidence that protein absorption is nm affected by olestra consumption.
The lack of an effect of olestra on fat ahsorpuon was demomtrated in studies conducted in rats and humans in which the amount of fat egcsred was compared to rhe amount ingested (14,17). In a representative clinical study Fallat et al ( 17) showed no difference 111 the perccnrage of fat ahsorbed with 50 g/day olcstra, either added to the diet or replacing 50 g fat in the diet. Other studies measuring recovery of radiolabelled triolein in the lymph of thoracic duct-cannulated rats rilso showed that olestra did not alter fatty acid absorption to any meaningful extent ( 15). Analysb of liver t issue from rats feJ a control diet or o lestra al 5°/i, of the Jiet for two years showed only minor differences in fatty acid composition, not attributable to olestra (20).
When considered together, these results support the conclusion that olestra does not interfere to any meaningful extent with lipolysis of t riglycerides or phospholipids, partitioning of products of lipolysis into the micellar phase, nor uptake of produces by cnterocytes.
O lestra d id not affect total lipid, phosphacidylcholine or phosphatidyl ethano lamine levels in the liver anJ kidneys of rats fed o lestra at l 0% of J ice
143
RER(;11011 el al
fo r three weeks, indica1 mg that n lestra docs not affect overall c ho line sta tus.
MINERAL ABSORPTION O lcstra would not he expec ted to
affect mine ra l ahs()rpt ilin ~incc
minerals arc n(1t lipid soluhlc and s ince o lestra docs not sapnnify in the gast rointestinal tract. As cxpectl'd ,
serum c hemistri es a nd analys is llf fern I calcium .ind magnesium in long te rm studies 111 anima ls and in c linical st u<lics have shown no d iffcn:ncc hetween cont rol nnd o lestrn groups.
VITAMIN ABSORPTION Early an ima l stud ies shliwcd that
h igh levels o f n lcstrn m u Id l()we r fatw luhle v irnmin ahsnrpt inn (35) . T he po tentia l rn affect ct hsorp t ion o f the fat
soluhle vitamins dqx:nds o n n numher of factors, among them the I ipid
solubili ty of the v itamin and the .imount nf n lcstra m the die t. Da ta o n vitamin srntus were collected in clin i
cal studies in which the o nly consistent effect was a decrease in serum vit am in
E levels to the low nnrma I range ( I 7, 3 I , 32,36-39). A recent 16 week study showed a 611c, dec rease in scrum vita min
E with dai ly ingestion l)f" 18 g/day o lesrra ( BP Koonsvitsky, Pn1ctc r & Gamble, unpublished data). Based nn these dma, supplemcntat i()n of o lestr:1 with lh1lpha-tncophcrol 1s proposed to
maintain nutrit ional equ iva lence rn vegernble n il , wh ich is a significant source llf v itamin E in rhe die t.
Additional cl inical research hns been cond ucted u~ing lnrgc- hnse sizes
and state-(if- the-art methods to e nsure that the nutritio nal stallls of othe r farsoluble vitam ins will nor he affected a t rhe levels of o lest rn consum ption expected for the uses proposed in chc cur
rent regulatory submiss io ns. In an investigat ion of the e ffect (1(
o lesrn.1 on vitamin l) stallls, 202 free
living adults consumed 20 g/day of o lestra 111 cookies fo r six weeb, as part of a diet supplemented with 760 iu/day
of vitamin Dz in order to measure e ffects o n absorptio n (40) . Scrum 25-
hy<lroxy-Dz le ve ls rose from bet ween 5.6 and 5.8 nmo l/L at haseline co 39.0
and 3 1.7 nmol/ L for the placebo .i nd olestra groups, respective ly, at week 6.
144
Rc l,uivc to phiccbo, scrum 25-hydmxyl)z lcveb were approxim,llcly 20%
lower in the o lestra group after two, four and six weeks. Scrum levels l)f 2 5-
h yd roxy-Dl were no t affected by o lcsrra n insumptio n.
S ince dietary vi ram in L) accounts for about l 01Xi of the to ta l pool, the cff cct o f 18 g/day nlestra on die tary v itnmin D ahsorpti<m would no t have a meaningful effect o n tota l vitamin D status. The nmtm lling factor in determining
v itamin D status is the production of vita m in D3 by the skin as H resu lt of sLmligh t exposure. This was confirmed in a 16 week study witho ut v irnmin D supplementat ion , which sho wed no di ffe re nce in serum levels of v itamin D (BP Koonsv itsky, Procter & G am hlc,
unpuhlishcd data ).
The effect of o lestra on vitamin K status was a bo invcst iga rcd in the s ixweek study described above ( 41 ) using
a sensit ive measure of v itamin K status, the serum concentration of func tional prothro m bin, measured by the S implasrin -Ecarin assay (42) . C louing rimes
.ind scrum ph ylloquine concent ratio ns were a lso measured .
There was no significan t differe nce herwecn grnups in levels of functio na l pro rhrombin measured by the S imp las
t in-Ecarm rn tio ; values were 0.80 and 0. 79 fc.H the o lesrra and placebo gro ups, re~pcctivcly, nt hascl ine, a nd 0.81 for hn th groups at study end . There was no s ignificant d ifference in change from bnscl inc lcveb of serum phylloquino ne when a nalyzed hy repeated measures. Proth rombi n t ime and pmtia l t hm mho plasr in t ime were unchanged over
the course of t he study and unaffected by o lestra. T he results indicate cha r c hronic ingestio n of o lest rn a t 20 g/day in the diet does no r affec t vit amin K status. S ince the re a re very limi ted
stores of vita min K and diet records sho wed low levels o f v itamin K inta ke, this srudy was a sensitive test of effects nf o lest ra o n vitamin K sta tus.
Human cl inical tests have shown that o lestra in the diet has li tt le o r no effec t on plasm.i v itamin A lcveb (39; EJ Schaeffer, Tufts Un ive rs ity , unpuhlish cd data) . A small base-s i:e study
showed no s ignific:rnr reductio n in plasma vitamin A levels when the
vitmni n was dissol vcd 111 nlcstra ( I 8 gin a mi lk shake) prior lO ingestion. l lowevcr, humam have l,1rge hepatic stores of vitam in A and thus plasma con
cencrnu ons dn not readi ly reflect changes in a hsorpt ion . Add itional swd1cs arc in progress to prov ide dat:i on the po tential of n lesrra ro affect vitam in A stores.
DRUG ABSORPTION Studies were abo conducted in rat~
and h umans wh ic h showed that o lestra d id nor affect ahsorption of lipophilK
d rugs. T he drugs tested included proprnnolol and the o ra l cnn traceptives, nnret hindrone and erhynyl cst r.id inl, which are among the mmt lip id slilublc.
Diazcpam (Val ium; Roche) was also
tested hecausc it is wide ly used . In one human study cnch drug hcing tested w~1s taken in a mi lk shake made with either 16 g n lestr,1, 16 g corn o il, or water. T he resu lts showed no d ifference
in amount absorbed o r in rime to peak scrum levels (4 3). Anochcr placeho
controlled crossover study which monitnrcd 28 women over two
menstrual cyc les showed that o lestra at
18 g/day d id nm affec t rhe ahsorprion or efficacy of a low do;.e ora l contraccpt ivc (Lo/Ovral-28; Wyeth) (44) .
ABSORPTION OF OTHER COMPOUNDS
I lalngenntcd hydrocarbons arc among the most l1pophdic of xcno
bimic subsrancl's and would rherefon: he pred icted to interact strongly wi1h olest ra. Dietary o ll'st ra has hcen shown to markedly reduce the absorpt ion ofan example of this cl,iss of compounds, 2,2-his (p-chlorophcnyl) I, I, I-trichloroethane (DDT), in an imals. A~ 1n
the case nf c ho lesterol, o lest rn rcd 11ced rhc absorpt io n of hoth d ietnry anJ 'endogeno us' DDT thm had hcen
stored in t he hody from prior feed ing. BaseJ on lymphatic collectio n of 1
\ ~
labellcd DDT. replaceme nt of 50% of the dietary SLlyhean oil with olcsrrn decreased dietary DDT absorption Ill
2 1.0±2 .4% from 66.6±l.9lX, in the rat (44). In a stud y o f previously deposited 14C-labclled DDT in gerbils, t he excre
t ion ()f 14C increased two- to t h reefold when olestra was included ns I 0% nt
CAN J G 1\t.;TROENTr-RUL VllL 5 N l l 4 Jut Y/AUl;U~T 1991
chc J 1et (46). C11mh111eJ w11h parri.11 food rc~tnct llll1, olestra effected ;111 up toc1ghrfolJ incrcasl' m L'Xcre1 i,m of tlw hhd. Thesl' re,uhs ,Hl' ums1sten1 w1th 1hc Jis,olut 10n nf DDT and its lirophilic mcrahnlitc intn the intestinal obtra ph,N:, thcreh\ reduc111g their ahsorption .mJ reah,orpuun. Eiod rc,tnction :1pp,1re11Ll) l11l1hili:ed these ,uhstance, from ,1J1posc ,rorage sire,.
CONCLUSIONS Results of cxren, 1vc resear ... h ,hm,
that okstra is cssclll 1ally inert 111 the ~astromlesliirnl tract, affcctmg nei ther morpholngy nnr function. It is not hydrolyzed hy ga,tm or panueauc lipN.'S anJ i, therefore nm ahsorhl'd . It 1s
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me1ahol ism J L1p1d Rt·, 1984;25: 1017-'it;. I lauton JC. l'lPm1ngn N, Mort1gl1l' M, ct al. A quanut,lll\ e dynam1t c,m.:ep1 n( thl· 1111npha,e p,1rt 1111n1 nf l1p1d,: AppliLat111111 0 h1k s.ilt lcu1h111 lholes1erol m1xt·d lllllL'lles. Rio<.:h1m1l' I 986;68:Z7'i-8'i
I Kubis A h11 Ah"1rpt11m, ,ol, I, II. R.x:J F.",1t1111: c 'Rl' Prl'", 1986.
4 Shim1 Y I·. I 1piJ digl'st11m :md ah,orpt1on In: Juhn,.,n LR. t·d Phy,1ology ,it d1l' ( '·"m11ntt·,t 1n.1l Traer. Nt·w York : l{.1ven l'rt>ss, 1987. Tho11N111 ABR, KL·,·lan 1\1, G1rg ML, Cl.111cl111m MT. lmt·,t 1n.1l ,ispL'Ll' <lf lipid ah,orpt 1<ln: In rL·,·1c,1. ( :,m J Phy,inl l'h.1r111arnl 1989;67: l 79 91.
o. T Sil!', S1mm<lnd., WJ The .1h,orpt1<111 ,,t lipid .111d lip<lpr<lll'lll ,ynthL',1s. L1p1d Re, Ml'I hod<1l 19M,V(.)l I 9 I l 16. Tso r. U,istrnintl'sllnal digL',ll<ln .md . 1h,orpt1on uf lipid. In: l'.1ok11 1 R, Kntchc,,k\ DR, L'<"- A,h ,llllL's m Lipid R,'S<'.lrt h. Nt·,1 Ymk: At .,dl'll11l Pres, I Ill, 1985
~- Vance DE. Vann: JI· B1ud1cm1,1 ry of lipid, .md memhra1w,. Tommo: ThL' l'>cnJ<lllllll ( 'u1111n1ng, l'uhli,hmg ( 'o
lnl, 1985 \Vark1m JB. L1p1,I d1g,·,11on .md ,1h,<lrpt 1< m l'L'd 1,11 nt, 1985;75 I: 151-6.
10 D1erschy JM. Wd,on JD. Rl·g1il,111"n .,f cholcst ,·rol mt·t,1hol 1,111 I. N l:nJ,!I J Med I 97L);Z82: 1128 l8.
II D1ctschy )M , Wil,011 JI). RL'gul.111<m "' , holc,tl'rol ml"L1h.1l 1,m 2 N l:ngl J McJ I 97L);l82: 1179 1' >
11 D1cc;,chy JM, Wils<l11 JI). Rcgulaunn nl chnle,terol mewhol1 ,m ~- N l:ngl J Mt·d I 97L\l82: I 241 -9
II Man,on HI, Volpt·nhL·1n RA
al,u n,H mct,1h1li:c.._l h, r,1lon1< .. micmflurn . ~ tudics of g,1',lm e mptying, bile ac 1d physiol, ig) ,md ,,anue,ll iL re,ponsL' 111JiL,lll.' th,ll o lcstra J,1,•, not affect these lutKtion,. NenhL'r doc.:, it altl'r thL' normal digestion and ahsnrrtion of mau,111utrient,, minerals o r ltpoph ii 1c drug,. ThL' ,1hs11rpuun of c holestcml and f,1t -sul11hle vnamllb, however, can he affectL·,1 wan l'\ll'lll Jetcrmmed hy the amo11n1 of o le,tra , the ltpophilil. it ) of the nutrient .ind other factlir,. Cl1111cal rc.:,earch t11,l.11e indtL,ltes chat okstrn I~ g/day del. rease, ,crum vitamin E level, to le\'ds still \\'llh 111 nnrmal range,, hut J11e, not affect ,·namtn 1) or K ,t,ltu~. Other ,rudll.'' arc assL'sstng rh...- l'fk•L ts of
I lvdmly,i, ,,t fullv es1,•rif1t·d ,ilu1huls u1111 ,1in111g fr<lm unt· to L'IJ.!ht lwdn,\\ group, by rhc lipolyt1t l'll"\llll'' of r,11 p,111,rl'at1t 1u1u'. J L1p1,I R,·, J<>7Z,l U25 8.
14. M.111"111 Fl I, Nulcn l,A Ah,urh.1hil1t) h\ r,1r, ,if <.:<lilll'<1und, <.:nn1.11n111i.: tn,m ,mt· 1,1 eight t·ster gn111p, J Nutr 1972;102:1171 6.
I 1. M,ur..un n I, \nlpcnlw111 RA R.11<.' .111<1 t·,tent 11f .,h,orptlllil ,,t thl' t.111\ ,1ud, nt fully t'st,·rilil'd glyn•rol, l'ryt hrit<ll. xyl 11 lll. .md s11Lr<1w .,, llll'il'llrcd 111 I hor.tLll du<.: I t ,11111Ul.1t l'd r.11,. J Nurr J •)7 2; WZ 1177 SO.
16. n .... rnh.1r,li l 'A l )lc,1r;1 A 111111 ·L,dPnl f.11 rq,lan'lllL'nt. Food T1:d1nol Int 191-iS: 176 K
17. F;ill,11 RW, (,lunk CJ, l.111mcr R, Mo111 ... ,11 t:11 :-;hort·tt'rlll ,,udy <ll SIil ru,e pol,t·,1,·r, .1 11rn1ah,Prhahle 1;11 lik, matt·n.il a, 1 d1,·1ar\ ,IJ.!t'lll t,11 l,1,H·r111g pl.1,m.1 <.:l111ie,1L·rol. Am J <'1111 Nurr I l/76;29: 1204 I 1
18. ( ,lul'Lk CJ, Ma11,011 r+. Jand,Kek RJ . fhe lowt·rmg uf pl,hlllil d1llle,tt·rol h ,u, n>s<.' pul\ e,1,·r 111 ,uhJt'L 1., l< 111,un1111g dit·t, with 8LX), \00 ,,r k·." 1han 'iO mg ,it d1nk,1<.'n1l pL'r d.n· 1\111 J l '1111 Nutr 1979; >2:16>6 44.
19. Wood FE, I lol ll'nh,1d1 l· I. K,1tft.11ht•rg,·r RM. L.1<.:k pf .ih,urp11un "' ole,t ra ( t )L) fllllm1111g drn in K
k'l·,lmg to r.u., .m,l munkt·y,. Fo· l<.1 ( 'hL'l11 Tox1rnl J l)l) I ;29:Z \ 1-6.
20. Wnod FE, l 1emq WJ. 1-.:ne:c, 1th Al , Bolt,· I If.. M,111rt·r JK, Hrt1lL' RI) l 'hmn1L 111)..1llt\ and t,11un,1gL•n1, 11\ ,111,li,·"11 llie,t ra 111 F1,dwr H4 r.11,. l·,11,ll lwml<>~1<.:ol i99J,29.2l\ IL\
21. Nokn ( ,A, WoPd l·E. I 11t'rLkma11 TA. A I wo-generat ll m reproducri,·e .ind dL'H'lopmcnt.il tu,1<.:1t\ stud\ of,uLmse polyL',rl'r. h11><.I ( 'ht·m Tn,Kol 1987;25:I 8
L·\~ j GA~11l\ lt ~ 111\\ 11 v, )[ 1 N114 Jt ·t Y/At '( ,t ·q J l)l) I
Review of studies of olestra
llle,tra 011 , tt.im111 t\ stnn·, lli dl.' tL't mme t hl' ,tppropn,ttenc,, of ,uppk
menr.11 i1lll. Thl're 1, tnn,·.i,111g l'\ 1dcnll' t h.1t
high 1111nke, of f,1t , i:,pect,illy s.1tun11ed fat, increase the risk of c.mliovasu1l.1r disease, ,md excl'" d1etar~ f,ll ts .1 con tnhuung factor 111 ,ihc.:suy. hypertl'n sit 111, adult on,cr diahetc,, and pn,hahl\' ,omc l ypes of cancer. The use of olc,t ra
and rn her fat replacers ha, the potent 1.1 I to hdp reduce l he J1l.'rt entagc of rn lone, from fat .md, 1mportancly, t hl' .1moun1 of saturn ted far in th i: J1et, hy inlrcasmg rhe avaih1hi lity of highly ,iv
ceprahle, fre4ucntl1 en ten food, l hat ,trL' ll1wcr 111 fat hut retmn thL' same ui,te and texturl' as full -fat coum erpan s.
22 Ad,11m MR, 1'v1tM.1h:111 MR, M,llts<llt Fl I.<. 'larbon TB. rill' long· term dkct, of dietary ,u,nhe polye,ter on Afnc,m green monkey,. Pro<. S,x: E:.,p B1ul Med 1981; 167: >46-5 >.
2 I M1lk-r KW. Wolld Fl:, Stu.ml SR, Al.kn l 'L TwL'lll\ month ok,tra feL·dmg study 111 dog,. rood ( 'hem T<l\ !LOI. (I I) Jll'l'"-)
24 J,111,L,n·k RJ. Tlw effect ,if 1111n,1h,orhahll' lipid, on dw 111rc~t1n,il .,h.,orpt 1<111 llf l1 pnphilc,. Drug Ml'tah R,·v 1982;13:695 714.
25. Cmtot f\, Ph1ll1p, SF, M.1lagd.1da JR (. ;,"tm empty111g ,if liquid ,lhL·r 111gL",t llm nf a ,olid l1qu1d nteal 111 hum,m, (. ,,htnx.·ntL'flllogy I% I ,S0:922-7
26. Cortot A, Ph11l1ps SF, Mal.1gL·l.1d,1 JR. Par,ilkl ga,UIL·L'lll)'ty ingof nonhydroly:ahk· f.11 .md 1\',llL'r ,tftL'r ,1 "'li,I liq111d lllL'ill 111 human,. U.1,t nil'ntcrology I 982;82:877 81.
27 I la,tlllJ.!' Ml I, t;lhnL'cman 1'10. l'an<.rL',ll IC en:ymt· and pl.1,111,1 Ll1nk,1t•rol re,pon,e to Lhrllnll mgt·,1 11111 of a non;ih,orhahk· l1p1d 111
rat,. Inst Nutr 1986;7:2!72 7 2,'i. M.11t"1n !'I I, Jand.1<.ek RJ. WL'hh MR
The dfe<.:t of .1 non.ihsorhahk• lipid, ,u<.:roS<' polyL",tcr, l 111 the ah,01 pl ion nf dietary lhnlc,tt'flll hy rhL· r;H J Nutr 1976;106:747 'i2
29 J,111d.1u·k RJ, M,111son HI, MrNel'i) '-i,
Uallnn I , Yunker R, Gl11L0Lk CJ. l:lktl of ,uln>SL' polyl'st,·r ,m fccal stl'ru1d L'X<.:rl'lhlll hy 24 mmnal llll'll Am I Clm Nutr 1980; \ U51-9.
10. UluL'Lk ( ·.1. J,md,1<.:l'k RJ. !->uhh1.il1 MTR, l't al. Etku of ,ulni,l' pohr,tL'r lll) kc1J h1Je ,ll Id L'X<:reflllll ,111d uHnp11si1 um 111 nu1 mal 1m·11. Am J Cl m N utr I 980; I U I 77 8L1.
\ I <.'mu'>l· JR, <.,rund1 SM. Hku, of ,utru,t· polycs1,·r,H1 <.hnll'ster11!
145
BERGHOLZ ec a/
metabolism 111 man. Metabolism 1982;35: 1352-9. Nutr 1991;53:943-6. 1979;28:994-1000. 37. Mel lies MJ, Jandacek RJ, Taulbee JD, 42. Suttie JW, Mummah-Schendel LL,
32. Grundy SM, Anasrnsia JV, Kes,11111:mi er al. A J ouhle-bl ind, placebo, Shah DV, Lyle BJ, Greger JL. Virnmm YA, Abram, J. Influence of sucnise controlled study of sucrose polyester in K deficiency from dietary vitamin K polyester on plasma lipoproteins, and hypercholesterolemic outpatients. restriction in humans. Am J Clin Nutr cholesterol metabolism in obese AmJ Clin Nurr 1983;37:339-46. 1988;47:475-80. patients with and without diabetes 38. Glueck CJ, Jandacek RJ , Hogg E, 43. Rubens RJ, Leff RD. Influence of mcll itus. Am J Clm Nutr Allen C, Bachler L, Tewksbury M. absorbahle and nonabsnrhablc lipids I 986;44:620-9. Sucrose polyester: Subst itution for and lipid-like suhstancc, on drug
33. Nuck BA, Federle TW. lnahd1ty of the dietary foes in hypocaloric diets in the hioava ilability. C lin Pharmacol Ther human colontc microflora w crcacmcnt of familial I 989;45:299-104. metabolize olestra. American Society hypercholesterolemia. Am J Clin Nutr 44. Mi ller KW, Williams DW, Carter SB, for Micrnb1<ll<igy, I 990;=073:275. 1983;37:34 7-54. J<mcs MB, Mishe ll DR. The effect ot (Abst ) 39. Mell ies MJ, Vitale C, Jandacek RJ, olcstra on ,ystcmic levels of oral
34. Jandacek RJ, Ramirez MM, Crouse JR. Lamkin GE, Glueck CJ. The contraceptives. Clin Pharmacol Thcr Effects of partial replacemenr of dietary substitution of sucrose polyester for 1990;48: 14-40. fat hy olesrra on dietary chnlestcrol dietary fat in obese, 45. Volpenhein RA, Wehh OR, Jandacck absorpt ion in man. Metabolism h ypercholestcrolemic outpatients. RJ. Effect of a nonahsorhable lipid, l 990;39:848-52. AmJ C lin Nutr 1985;41: l -12. , ucro,e polyester, on the absorption of
35. Mamon FH, Hollenbach EJ, 40. Jones DY, Miller KW, Koonsvitsky BP, DDT by the rat. J Toxicol Environ Kuehlthau CM . The effect of a er al. Scrum 25-hydroxyviramin D Health 1980;6:679-83. nonahsorhahlc far, , ucrosc polye,rer, levels of free-living subjects consuming 46. Murrer LC, Blanke RV, Jandacck RJ, on rhc mcrnholism of vitamin A hy the olestra. Am J Clin Nutr Guzelian PS. Reduction in the body rat. J Nutr 1979; 109: 1688-93. !991;53:1281-7. content of ODE in the Mongolian
36. Glueck CJ, Hastmg, MM, Allen C, 41. Jones DY, Miller KW, Koonsvitsky BP, gerbi l treated with sucro,e polyester ct al. Sucrose polye,ter and coven et al. Vitamin K status of free-living and caloric restriction. Toxicol calmic Jilution. Am J Clin Nutr subjects consuming olcstra. Am J Clin Applied Pharmacol I 988;92:428-35.
146 CAN J GA'-TR()r'\cTLJ(UI Vol 5 Nl \ 4 Jllt.Y/AU(;UST I \191
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