The Effects of Bile Acid Feeding on the Development of Ileal Bile Acid Transport

Shneider, Benjamin L.; Michaud, Gregory A.; West, A. Brian; Suchy, Frederick J.

doi:10.1203/00006450-199303000-00002

Cited by 25 publications

(15 citation statements)

References 14 publications

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“…Oatp1 mRNA expression is first detected on day 16 of gestation, remaining stable during the perinatal period and increasing dramatically after weaning (Dubuisson et al, 1996). The increase of both oatp1 and oatp2 expression after weaning might be attributed to the dramatic increase in bile acid concentrations in serum at this age (Belknap et al, 1981;Suchy et al, 1981;Shneider et al, 1993Shneider et al, , 1995. The postnatal development of Na ϩ -dependent taurocholate-cotransporting polypeptide, the Na ϩ -dependent hepatic bile acid uptake transporter, seems to occur earlier than the development of oatp1 and oatp2.…”

Section: Discussionmentioning

confidence: 99%

Postnatal Expression and Induction by Pregnenolone-16α-Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver

2002

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ABSTRACT:Newborn rats are more sensitive to the toxic effects of cardiac glycosides than are adult rats. This is associated with a decreased ability to remove cardiac glycosides from blood into the liver. Pregnenolone-16␣-carbonitrile (PCN), a prototypical rodent CYP3A inducer and pregnane-X-receptor (PXR) ligand, stimulates the hepatic clearance of cardiac glycosides in newborn rats, which results in decreased toxicity of the cardiac glycosides. The mechanism responsible for this phenomenon is not clear; however, if elucidated, it would help in understanding and preventing potential drug-drug interactions. The recently cloned rat organic anion-transporting polypeptide 2 (oatp2) (Slc21a5) is a sinusoidal hepatic uptake transporter, with very high affinities for cardiac glycosides, and thus it was hypothesized that rat oatp2 increases during postnatal development and is inducible by PCN. In the present study, livers were removed from Sprague-Dawley rats from postnatal days (pnd) 0 to 45, in 5-day increments; as well as from pnd 10 to 90, in 10-day increments, after PCN (75 mg/kg i.p., for 4 days) or corn oil (vehicle for PCN) treatment. The protein and mRNA levels of rat oatp2 were determined by Western blot analysis and branched DNA signal amplification technique, respectively. Expression of rat oatp2 protein and mRNA increased gradually during postnatal development. PCN treatment increased liver to body weight ratio in both genders, and dramatically accelerated the maturation of hepatic oatp2 protein and mRNA levels. In summary, rat oatp2 undergoes age-dependent and chemical regulation during postnatal development, and is a potential target for drugdrug and age-drug interactions.Compared with adult rats, newborn rats are more sensitive to the toxicity elicited by cardiac glycosides, such as ouabain and digoxin (Klaassen, 1972(Klaassen, , 1973. This is associated with the decreased ability of the liver in newborn rats to remove cardiac glycosides from the blood, thereby causing greater toxicity in newborn rats (Klaassen, 1972). The mechanism of toxicity has been further characterized by showing that the rodent CYP3A inducer pregnenolone-16␣-carbonitrile (PCN 2 ) increases hepatic clearance of cardiac glycosides in newborns, thus reducing cardiac glycoside toxicity (Klaassen, 1974a,b). The kinetics of ouabain uptake in isolated hepatocytes from rats at various ages demonstrates that V max increases with age, suggesting an increase in uptake transporter(s). Although there is no statistical difference in the K m of ouabain uptake in hepatocytes during development, the K m tended to be higher in the young rats, suggesting the involvement of two transporting systems (Stacey and Klaassen, 1979).Further understanding of the hepatic uptake of cardiac glycosides was made possible by the recent advances in the cloning of the rat organic anion-transporting polypeptide 2 (oatp2) (Slc21a5) (Noe et al., 1997). Rat oatp2 is expressed in the hepatic sinusoidal membrane (Noe et al., 1997;Abe et al., 1998Abe et al., , 1999Gao et...

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Section: Discussionmentioning

confidence: 99%

Postnatal Expression and Induction by Pregnenolone-16α-Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver

2002

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“…Sodium 10 mM HEPES (pH 7.4). After incubating for 15 min at 37°C, the cells were washed three times with 1.0 ml of ice-cold choline containing incubation buffer and lysed with 0.5 ml of 0.5% Triton X-100 in water.…”

Section: Methodsmentioning

confidence: 99%

“…Ileal brush border membrane vesicles (BBMV) 1 were prepared from rat ileum by divalent cation precipitation as described previously (10). Approximately 2-4 mg of these ileal BBMV were solubilized in 50 mM n-octyl-␤-D-glucopyranoside (OGS), 1 M NaCl, 10 mM Tris, pH 8.0, for 2.5 h at 4°C and spun at 100,000 ϫ g; then, the supernatant was diluted to 15 mM OGS before applying to the bile acid affinity column.…”

Section: Methodsmentioning

confidence: 99%

Cloning and Characterization of a Novel Peptidase from Rat and Human Ileum

Shneider

Thevananther

Moyer

et al. 1997

Journal of Biological Chemistry

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A novel 100-kDa ileal brush border membrane protein (I100) has been purified by anionic glycocholate affinity chromatography. Polyclonal antibodies raised against this protein were utilized to clone and characterize I100 in rats. A partial length human I100 cDNA was identified by hybridization screening. In the rat, the I100 protein is a 746-amino acid glycosylated (calculated core molecular mass of 80 kDa) type II integral membrane protein found on the apical surface of ileal villus enterocytes. Its 2.6-kilobase mRNA is expressed in distal small intestine in rats and in humans. The I100 cDNA is homologous to but distinct from human prostate-specific membrane antigen and rat brain N-acetylaspartylglutamate peptidase. It is expressed on both the basolateral and apical surfaces of stably transfected Madin Darby canine kidney cells. Analysis of these stably transfected Madin Darby canine kidney cells and I100 immunoprecipitates of rat ileal brush border membrane vesicles reveals that it has dipeptidyl peptidase IV activity. Future invesitgations will need to determine the exact substrate specificity of this novel peptidase.

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“…In the intestine, both upregulation in pup rats 37 and downregulation in the adult rat 38 have been described. In the adult, exposure of the liver to a high bile salt flux can increase the SR max for taurocholate.…”

Section: Morphological Alterations In Offspring Ofmentioning

confidence: 99%

Reversible impairment of neonatal hepatobiliary function by maternal cholestasis

et al. 1996

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importance of the implications derived from these findThe effect of total blockage of maternal biliary excreings both in the nutrition and management of human tion during the last third of the pregnancy on the matuneonates demands further evaluation of the hepatobiliration of hepatobiliary function was investigated in neoary function of babies born after alterations of fetal-manatal rats. Extrahepatic obstruction of the common bile ternal bile acid homeostasis, such as in maternal obstetduct on day 14 of pregnancy induced a marked enhanceric cholestasis. (HEPATOLOGY 1996;23:1208-1217.) ment in serum bilirubin-mainly conjugated bilirubinand bile acid concentrations as compared with shamoperated pregnant rats. Excretion of bile acids by the Normal fetal development requires efficient transfer kidney was significantly increased, whereas fecal elimi-across the placenta. Nutrients are supplied by the nation of these compounds was almost abolished. Most mother while certain potentially toxic compounds cross of the cholestatic mothers (CMs) (77%) were able to carry the placenta, mainly in the fetus-to-mother direction. pregnancy to term and lactation until weaning (21 days Among the latter are bile acids. Both in humans and after birth). The body and liver weights of their offspring experimental animals, the onset of bile acid biosynthewere lower than for offspring of control healthy mothers sis precedes the development of efficient mechanisms in all postnatal periods considered. Serum bile acid concentrations were higher in the fetuses and neonates of involved in enterohepatic circulation.1 Hepatic insuffiCMs. This difference was evident up to 1 week after ciency with respect to bile acid secretion is found in weaning and disappeared in young adult animals (8 both premature and full-term infants.2 This is accomweeks old). When the bile secretion rate was investi-panied by a marked immaturity of small intestinal gated in these animals at 4 or 8 weeks of age, no signifi-transport of bile acids. [3][4][5] Because the accumulation of cant difference was found as far as nonstimulated bile bile acids within the fetus can seriously challenge the flow and bile acid output was concerned. However, the viability of pregnancy, such compounds must be transbiliary response to stepwise sodium taurocholate (TC) ferred to the mother, whose liver is able to excrete them intravenous infusion showed that 4-week-old neonates into bile. Therefore, fetal-maternal bile acid homeostaof CMs had impaired bile acid secretion. Moreover, the sis requires both functional placental transfer and normaximal secretion rate (SR max ) for TC was significantly reduced (030%), whereas the choleretic ability of tauro-mal maternal hepatobiliary function. cholate was not modified. This alteration was not selec-Obstetric cholestasis is a pathological situation chartive for bile acids. The SR max for bromosulfophthalein acterized by a 10-to 100-fold increase in postprandial (BSP) was also significantly lowered (040%). These dys-bile acid concentrations in the m...

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The Effects of Bile Acid Feeding on the Development of Ileal Bile Acid Transport

Cited by 25 publications

References 14 publications

Postnatal Expression and Induction by Pregnenolone-16α-Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver

Postnatal Expression and Induction by Pregnenolone-16α-Carbonitrile of the Organic Anion-Transporting Polypeptide 2 in Rat Liver

Cloning and Characterization of a Novel Peptidase from Rat and Human Ileum

Reversible impairment of neonatal hepatobiliary function by maternal cholestasis

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