Biomedical subjects

I M Yousef

Publications and source records attributed to I M Yousef.

At least 37 records · Page 2Linked to original sources

PubMed1995

1-Naphthyl isocyanate and 1-naphthylamine as metabolites of 1-naphthylisothiocyanate.

The importance of the bioactivation of 1-naphthylisothiocyanate was studied. Forty minutes after 1-naphthylisothiocyanate administration to rats, bile was collected over a 2.5-h period; the liver was then excised and homogenized. 1-naphthylisothiocyanate and its metabolites in bile and liver of rats were identified and quantified using coupled gas chromatography-mass spectrometry. Three main compounds were found in all 1-naphthylisothiocyanate-treated animals. They were identified as 1-naphthyl isocyanate, 1-naphthylamine and the parent compound, 1-naphthylisothiocyanate. When rats were given cycloheximide, which attenuates 1-naphthylisothiocyanate toxicity, 30 min before 1-naphthylisothiocyanate (300 mg/kg), 1-naphthyl isocyanate concentration was significantly lower than in rats receiving only 1-naphthylisothiocyanate. The appearance of 1-naphthylamine was also inhibited by cycloheximide, although not to the same extent as 1-naphthyl isocyanate. On the other hand, phenobarbital, which potentiates 1-naphthylisothiocyanate hepatotoxicity, enhanced 1-naphthyl isocyanate and 1-naphthylamine formation. It is suggested that 1-naphthyl isocyanate, 1-naphthylamine and the highly reactive sulfur released from 1-naphthylisothiocyanate might be involved in the hepatotoxic effect of 1-naphthylisothiocyanate.

1-Naphthylamine↗

PubMed1994

Short-term feeding of a diet enriched in phospholipids increases bile formation and the bile acid transport maximum in rats.

Earlier studies suggested that the secretory rate maximum (SRm) of bile acid and the cholestasis which occurs after the SRm is reached may be determined by the hepatic or extrahepatic biliary phospholipid pool. We therefore investigated whether bile formation and the bile acid SRm could be influenced by feeding a diet enriched in phospholipids. Male rats were fed phospholipid (PLD) or triacylglycerol (TgD)-enriched diet for 3 days, and bile formation as well as biliary lipid output were measured on the 4th day. In other similarly fed groups, cholic acid was infused in stepwise increasing doses to determine the effect of PLD on the SRm of cholic acid. The plasma lipid levels were significantly lower in PLD and TgD diets compared to basal diet. But, while the levels of total cholesterol (CH), HDL-CH, and phospholipid (PH) were not significantly altered by PLD compared to TgD, the triacylglycerol levels were markedly increased by PLD. In the liver of PLD fed rats, triacylglycerol and CH ester contents decreased by 39 and 62%, respectively, while free CH and PH contents were not significantly changed. The PLD significantly augmented spontaneous bile flow, bile acid, PH and CH secretion rates compared to TgD diet (65, 124, 164 and 654%, respectively). The enhanced biliary secretory function was associated with an increase in pericanalicular vacuoles and diverticuli in centrilobular hepatocytes. Compared to TgD fed rats, PLD rats showed a 2-fold decrease in the ratio of cholic acid/chenodeoxycholic acid in bile and a significant decrease in the % contribution of taurine conjugated BA. The PH fatty acids in bile were similar in both groups except that in PLD group the % contribution of C18:2 was higher than in TgD group. No differences were found in plasma membrane CH/PH content or total fatty acid composition. During bile acid infusion, the SRm and the total cholic acid secreted were significantly higher in the PLD than in the TgD rats. Moreover, the cholestatic response observed after high bile acid dose was markedly reduced by PLD. The results show that short-term feeding of PLD induces changes in CH and bile acid metabolism which result in enhanced biliary output of CH and PH. The enhanced pool of biliary lipid may protect plasma membranes from the deleterious effects of high bile acid concentrations.

Animals↗

PubMed1994

Phase I and phase II metabolism of lithocholic acid in hepatic acinar zone 3 necrosis. Evaluation in rats by combined radiochromatography and gas-liquid chromatography-mass spectrometry.

In the present study, lithocholic acid (LCA) metabolism was assessed by radiochromatography and gas-liquid chromatography-mass spectrometry, and its relationship to cholestasis was investigated. In addition, the role of the perivenous zone in LCA-induced cholestasis and LCA biotransformation was examined by using bromobenzene (BZ), a chemical that causes selective necrosis of hepatocytes in this zone. LCA injection induced cholestasis of comparable amplitude in both control and BZ-treated rats. The biliary recovery of bile salts (BS) was 65-70% 2 hr after LCA injection. Excretion of LCA and its cholestatic metabolite, LCA glucuronide, was similar in both groups, although LCA excretion was delayed in BZ-treated animals. The appearance of LCA and LCA glucuronide in bile occurred early, and their proportion decreased with time. Concentrations of choleretic hydroxylated metabolites were low immediately after LCA injection but increased with time. 3 alpha,6 beta-Dihydroxy-5 beta-cholanoic and 3 alpha,6 beta,7 beta-trihydroxy-5 beta-cholanoic acids were the major species arising from LCA, indicating the importance of 6 beta hydroxylation in LCA detoxification in rats. Other metabolites were found, but their contribution was either minor or negligible. Overall amounts of hydroxylated metabolites were comparable in both groups, but trihydroxylated metabolites predominated over their dihydroxylated counterparts in control rats, whereas the production of dihydroxylated forms was more pronounced in BZ-treated animals. These results suggest that the destruction of perivenous hepatocytes does not exacerbate LCA-induced cholestasis, and that there may be an acinar zonation of LCA biotransformation to trihydroxylated metabolites in the rat liver.

Animals↗

PubMed1994

Decreased biliary glutathione content is responsible for the decline in bile salt-independent flow induced by ethinyl estradiol in rats.

Glutathione appears to be a major osmotic factor in the generation of bile salt-independent flow (BSIF). This study was designed to investigate its importance in the pathology of 17-alpha-ethinyl estradiol (EE)-induced cholestasis. Five-day EE treatment at the dose level of 5 mg/kg/day significantly decreased bile flow (57% of controls) and biliary glutathione secretion. Evaluation of the contribution of bile salt dependent flow (BSDF), glutathione dependent flow (GSDF) and the bile flow generated independently of both bile salts and glutathione (BS-GSIF) revealed that EE decreased all portions of the flow (63, 44 and 52% of control values, respectively). At 4 and 20 h after a single administration of the same EE dose, a significant diminution of bile flow was noted (decreases of 17 and 29%, respectively) in association with a significant fall in biliary glutathione content. Under these conditions, BSDF and BS-GSIF were not modified (98 and 112% of control BSDF values, respectively; 96 and 99% of control BS-GSIF values, respectively) while GSDF was decreased markedly, representing 65 and 50% of control values. Biliary glutathione secretion was diminished without modification of liver and blood glutathione concentration or redox status following single EE dose whereas, after 5 days of EE treatment, a significant increase in liver glutathione was observed, suggesting that EE may interfere with the glutathione secretory process. This study demonstrates that EE rapidly alters biliary glutathione content, leading to a marked decline in GSDF. This reduction may explain the decrease in BSIF produced by EE at the outset of cholestasis.

Analysis of Variance↗

PubMed1994

Protection by indomethacin against the lethality and hepatotoxicity of phalloidin in mice.

The present study examined the possible involvement of endogenous cyclooxygenase-derived factors in the lethality and hepatic hemorrhagic necrosis induced by phalloidin. Mice were pretreated with indomethacin, aspirin or ibuprofen (all inhibitors of cyclooxygenase) and injected with phalloidin (2 mg/kg). The toxin induced 75% lethality and caused severe hemorrhagic necrosis of the liver associated with increased serum levels of AST and ALT. Indomethacin completely prevented the mortality and hepatic damage elicited by phalloidin as judged by morphologic analysis and serum AST and ALT release. The in vitro addition of indomethacin to suspensions of freshly-isolated hepatocytes decreased plasma membrane bleb formation induced by phalloidin. In contrast to indomethacin, aspirin and ibuprofen did not influence phalloidin toxicity in vivo. These results suggest that inhibition of prostanoids per se may not be the sole mechanism of protection by indomethacin.

Alanine Transaminase↗

PubMed1994

Moderate long-term physical activity improves the age-related decline in bile formation and bile salt secretion in rats.

This study examined the effect of moderate long-term exercise, begun soon after weaning, on the age-related decline in bile formation and the secretory rate maximum (SRm) of taurocholate (TC), the major bile salt (BS) in rats. Eight-month-old sedentary (S) female Sprague-Dawley rats showed a significant decrease in basal and TC-stimulated bile formation when compared with 2.5-month-old S controls. As in younger rats, decreased biliary phospholipid (PL) output was associated with the TC SRm, but this change appeared much more rapidly in S animals, which also exhibited significant increased plasma lipids and higher TC concentrations in plasma and liver at the end of the TC infusion. Exercise significantly improved bile flow (BF), including the bile salt-dependent and -independent fractions under basal and TC-stimulated conditions in 8 month-old rats. Although all the biliary parameters evaluated were improved, maximal BF and PL secretion values were affected the most and were virtually not different from those obtained in younger S animals. Exercise also significantly lowered the age-related elevation of plasma PL. Thus, moderate long-term exercise exerts a beneficial effect on hepatobiliary function and the BS SRm, an effect that may be attributed in part to increased availability of a biliary PL pool previously implicated in regulation of the BS SRm.

Age Factors↗

PubMed1993

Pan-sulfation of bile salts markedly increases hydrophilicity and essentially abolishes self- and hetero-association with lecithin.

In chronic liver disease, partially and to a lesser extent completely (pan-)sulfated common bile salts are synthesized, yet little information is available concerning their physical-chemical characteristics. We studied solution properties of pan-sulfated common free, taurine and glycine-conjugated bile salts, and the interactions of taurodeoxycholate di-sulfate (TDC-S) with lecithin. By reverse-phase HPLC, pan-sulfated glycine and taurine-conjugated bile salts were very hydrophilic, with hydrophobic indices 1.7 to 2.5 units lower than their non-sulfated congeners. In contrast to non-sulfated species, pan-sulfated free and glycine-conjugated bile salts produced simple potentiometric titration curves without precipitation of bile salt below the pK'A of the carboxylic acids. By quasi-elastic light scattering, critical micellar concentrations of TDC-S fell from 28 mM in 0.15 M NaCl to 3 mM in 4.0 M NaCl, a value slightly higher than that of TDC. TDC-S formed very small micelles (hydrodynamic radii approx. 11A) that, in contrast to TDC, did not grow with increases in bile salt (7-66 mM) or NaCl (0.15-2.0 M) concentrations. TDC-S formed mixed micelles with lecithin in 0.15 M NaCl, but with a micellar zone drastically reduced compared with that of the non-sulfated congener. However, in 4 M NaCl, the micellar zone of TDC-S expanded and approached that of the non-sulfated parent compound. Therefore, under physiological conditions, pan-sulfation of common bile salts should largely eliminate their capacity to form mixed micelles with membrane lipids.

Bile Acids and Salts↗

PubMed1993

Influence of oral treatment with ursodeoxycholic and tauroursodeoxycholic acids on estrogen-induced cholestasis in rats: effects on bile formation and liver plasma membranes.

In this study, we examined whether ursodeoxycholic acid (UDC) and its taurine conjugate, tauroursodeoxycholic acid (TUDC), given per os, can prevent the cholestasis induced in rats by 17-alpha-ethynyl estradiol (EE) and whether this protection is mediated by choleretic activity or altered plasma membrane composition. EE (5 mg/kg body weight/day for 5 days) markedly reduced bile flow and bile salt secretion without significantly affecting plasma membrane composition and function. Treatment with UDC or TUDC (100, 150 or 200 (TUDC only) mumol/100 g body weight/day for 5 days) did not significantly modify bile flow, but the bile salt secretion rate increased in a dose-dependent manner. UDC was the main biliary bile acid secreted in groups given higher doses of UDC or TUDC. At these dose levels, bile acid treatment did not affect plasma membrane fluidity as assessed by fluorescence anisotropy, the cholesterol/phospholipid molar ratio as well as Na+K(+)- and Mg(++)-ATPase activities. The highest dose of UDC and TUDC prevented the reduction of both bile flow and bile salt secretion induced by EE, re-establishing these parameters to the values of the corresponding control for the UDC group. In conclusion, UDC and TUDC, given per os, improve EE-induced cholestasis, an effect that cannot be attributed to choleretic activity or altered plasma membrane composition.

Administration, Oral↗

PubMed1992

Pathogenesis of lithocholate-induced intrahepatic cholestasis: role of glucuronidation and hydroxylation of lithocholate.

It has been shown that lithocholic glucuronide is more cholestatic than lithocholic acid (LCA), as well as its taurine and glycine conjugates. Furthermore, LCA hydroxylation is thought to be a major detoxifying mechanism. Therefore, the role of LCA glucuronidation and hydroxylation was investigated during the development of LCA-induced cholestasis and recovery from it. Male rats received a bolus intravenous injection of [14C]LCA (12 mumol/100 g body weight) and bile samples were collected every 30 min for 5 h. Bile flow (BF) was reduced immediately after LCA injection, dropping to 40% of basal BF at 60 min. It then started to increase, reaching normal bile flow values at 3.5 h. Morphologically, canalicular lesions were dominant at 60 min and virtually absent at 2 h. At 60 min (maximal cholestasis), 30% of the LCA injected was secreted in bile, 20% was found in plasma while the other 50% was recovered in the liver and distributed mainly in plasma membranes, microsomes and cytosol. At the end of the experiment (normal BF), 20% of the LCA injected was still in the liver but was present mainly in the cytosol. In bile, within 30 min after injection, 46% of the LCA secreted was lithocholic glucuronide, 24% was conjugated with taurine and glycine, and 21% was in the form of hydroxylated bile acids. During the recovery period, lithocholic glucuronide secretion decreased to 18-25%. Taurine and glycine conjugate secretion increased to a maximum of 43% at 60 min, after which it was reduced to 21-28%. In contrast, hydroxylated metabolites were elevated during the recovery periods, reaching a maximum (45%) at 120 min and remaining constant thereafter. These results suggest that: (i) LCA binding to plasma membranes and microsomes appeared to correlate with the development of cholestasis; (ii) LCA glucuronidation may initiate and/or contribute to LCA-induced cholestasis; and (iii) hydroxylation predominates during recovery from cholestasis.

Animals↗

PubMed1992

Tight junction permeability and liver plasma membrane fluidity in lithocholate-induced cholestasis.

The present study correlated the reversibility of bile flow (BF) impairment with biochemical and morphological changes in the liver after injection of a cholestatic dose (12 mumole/100 g body weight) of lithocholic acid (LCA). BF declined maximally at 60 min but recovered totally at 210 min after LCA treatment. During the cholestatic period, there was an increase in tight junction permeability as measured by the bile to plasma (B/P) ratio of inulin and using lanthanum as a tracer. Cholesterol content and the cholesterol/phospholipid ratio in liver plasma membranes (LPM) were augmented while the fluidity of bile canalicular membranes (BCM) was decreased at 30 and 60 min after LCA injection. These changes in cholesterol content and membrane fluidity seemed to be correlated with LCA incorporation in LPM; their reversal at 120 min preceded the recovery of BF (210 min). Some biochemical disorders were evident after LCA injection, but they did not correlate with the variation in BF. These data suggest that increased tight junction permeability and decreased BCM fluidity are important pathogenic steps in LCA-induced cholestasis.

Animals↗

PubMed1992

Potentiation of lithocholic-acid-induced cholestasis by methyl isobutyl ketone.

Methyl isobutyl ketone was found to potentiate intrahepatic cholestasis induced by taurolithocholate and the combination of manganese-bilirubin. The aim of this study was to elucidate the mechanism of this potentiation using the lithocholate-induced cholestasis model. Male rats were given methyl isobutyl ketone 7.5 mumol/kg body wt. daily for 3 days. The effect of this treatment on lithocholate-induced cholestasis, bile formation and taurocholic acid transport was examined. The data showed that methyl isobutyl ketone treatment potentiated lithocholate-induced cholestasis and reduced significantly bile salt, phospholipid and cholesterol secretion rates as well as the transport maximum of taurocholic acid. It is suggested that methyl isobutyl ketone potentiates lithocholate-induced cholestasis by reducing the bile salt pool and interfering with the haptic secretion rate of bile salts.

Animals↗

PubMed1992

Do intracellular Ca2+ activity and hepatic glutathione play a role in the pathogenesis of lithocholic acid-induced cholestasis?

The possible relevance of alterations in intracellular Ca2+ and hepatic glutathione levels (GSH) in the pathogenesis of cholestasis induced by lithocholic acid (LCA) was examined by comparing effects of LCA and acetaminophen on these parameters and bile flow (BF) in rats. Intracellular Ca2+ activity was measured via glycogen phosphorylase a determination in rats given an intravenous bolus injection of either LCA (12 mumol/100 g body wt.), acetaminophen (60 mg/100 g body wt.), or a mixed solution of LCA and acetaminophen. BF was reduced immediately after LCA administration, with a maximum decrease occurring at 60 min followed by an increase to normal values at 210 min. On the other hand, glycogen phosphorylase a activity was elevated during all time periods after LCA treatment. Hepatic glutathione followed the BF curves being markedly depleted at the peak of cholestasis (60 min) and normal in the total recovery period (210 min). In contrast, acetaminophen had no effect on BF but significantly increased glycogen phosphorylase a activity and depleted hepatic glutathione levels. These results suggest that cholestatic effect of LCA is not due to changes in intracellular Ca2+ or hepatic glutathione levels.

Acetaminophen↗

PubMed1992

Low protein diets potentiate lithocholic acid-induced cholestasis in rats.

Earlier studies showed that low protein diets (LPD) reduce bile flow and bile acid secretion. We therefore examined the effect of LPD on lithocholic acid (LCA)-induced intrahepatic cholestasis. Female Sprague-Dawley rats were fed LPD (8% casein) soon after weaning for 4 or 12 wk, and then were injected intravenously with a single dose of LCA (4 mumol/100 g body wt). Bile was collected for 30-min periods, and bile flow as well as biliary lipid secretory rates were measured. Bile acid metabolism was also studied and the results were compared with those obtained in rats fed an adequate protein diet (26% casein). The LPD produced significantly lower bile flow and bile acid secretion, which were attributed to a reduced bile acid pool and a reduction in synthesis. They also enhanced the LCA-induced decline in bile flow, and rate of biliary output of total bile acids, phospholipids and cholesterol. The LPD were also associated with impaired LCA secretion in bile and increased retention in plasma and liver. Studies of LCA metabolism in rats fed a LPD indicated lower hepatic LCA hydroxylation, a greater percent contribution of glyco conjugates and lower levels of tauro conjugates. The present findings suggest that the reduced bile acid pool size, diminished LCA excretion and biotransformation to less toxic bile acids may explain the greater cholestasis in LPD-fed rats.

Animals↗

PubMed1991

Hepatic drug metabolism during development in food-restricted female Sprague-Dawley rats.

Hepatic drug metabolism was investigated in female Sprague-Dawley rats fed ad libitum (A) or a restricted diet (R) (implemented from age 1 month), at 1.5, 4.5 and 12 months to determine the short- and long-term effects of caloric restriction. Microsomal cytochrome P-450 content and NADPH cytochrome c reductase activity were not modified by age. While dietary restriction did not affect cytochrome P-450, it significantly increased NADPH cytochrome c reductase activity at all time periods when compared to corresponding A-fed groups. Aniline hydroxylase and aminopyrine N-demethylase activity tended to decrease with age in the A-fed groups but the differences did not prove to be statistically significant. A significant decrease of aminopyrine N-demethylase was observed with age in R rats. A significant reduction of aniline hydroxylase activity was noted in the R groups compared to age-matched A-fed controls. In contrast, aminopyrine N-demethylase activity increased significantly, but only at 1.5 months of age. Glutathione S-transferase activity was augmented between 1.5 and 4.5 months of age, and this was followed by a significant decrease at age 12 months in both A and R groups. Dietary restriction had no effect on this enzymatic activity. The microsomal cholesterol and phospholipid content as well as the cholesterol/phospholipid molar ratio changed significantly between 1.5 and 4.5 months of age but not between 4.5 and 12 months of age. These parameters were unaltered by dietary restriction. In conclusion, in the female Sprague-Dawley rat there are no statistically significant changes in hepatic microsomal components and drug metabolizing capacity between 1.5 and 12 months of age. Dietary restriction resulted in significant changes in enzymes related to drug metabolism which varied with the enzyme examined. In general, these changes were similar after short- or long-term dietary intervention.

Aging↗

PubMed1991

The effect of taurine on the cholestatic potential of sulfated lithocholate and its conjugates.

The present study was aimed at determining whether the protection by taurine of lithocholate-sulfate-induced cholestasis is mediated by conjugation or by direct effect of the amino acid on bile formation. Injection of free and conjugated (glycine and taurine) sulfated lithocholate in guinea pigs significantly reduced the secretion rate of non-sulfated bile acids in bile. There was no decrease in bile flow after the injection of taurine-conjugated sulfated lithocholate, which was completely recovered in bile within 60 min. In contrast, injection of sulfated lithocholate and its glycine conjugate led to a marked decrease in bile flow, and neither one was significantly recovered in bile. In addition, both caused morphological changes in the liver, characterized by the accumulation of cytoplasmic vacuoles with lamellated myelin figures characteristic of phospholipidosis. Pretreatment with taurine (0.5% in drinking water for 3 days) prevented both the drop in bile flow and the histological changes in the liver, suggesting that conjugation with taurine removed the cholestatic potential of sulfated lithocholate. However, since taurine was effective not only in preventing cholestasis induced by the free form of sulfated lithocholate but also against its glycine conjugate, these results suggest that other mechanisms in addition to conjugate must be involved.

Animals↗

PubMed1990

Effects of bile acids on actin polymerization in vitro.

Bile acids are major determinants of canalicular bile secretion, and there are indications that choleretic bile acids increase bile canalicular contractions, in isolated rat hepatocytes. Therefore, we examined the influence of various bile acids on the rate of actin polymerization in vitro. The free forms of cholic acid, ursodeoxycholic acid, and chenodeoxycholic acid, as well as their taurine and glycine conjugates, were incubated with purified muscle actin, at a concentration of 100-300 nmoles/mg actin. The rate of actin polymerization was measured by viscometry and the fluorescence of the pyrene probe, linked to actin. Results showed that all bile acids slow the rate of polymerization, and that the effect was dose-dependent. However, the reduction by chenodeoxycholic acid was greater than that caused by the other bile acids. The results indicate that bile acids, particularly in high concentrations interact with actin, a finding that may be related to the increased bile canalicular contractility, and altered canalicular membrane morphology, induced by choleretic bile acids.

Actins↗

PubMed1990

The role of acinar zone 3 hepatocytes in bile formation: influence of bromobenzene treatment on bile formation in the rat.

The role of zone 3 hepatocytes in bile formation was determined when they were selectively destroyed by 3.8 mmol/kg b.w. of bromobenzene injected i.p. for 48 h, as compared to appropriate controls. Bromobenzene treatment resulted in 29 +/- 4.4% hepatic lobule necrosis localized in the zone 3 hepatocytes. Although bile flow and bile salt-independent flow were not affected, this treatment was associated with a significant reduction in bile salt, and phospholipid secretion. The bile salt pool and bile salt synthesis were also significantly decreased. These results suggest that necrosis of zone 3 hepatocytes induced by bromobenzene reduced bile acid synthesis which decreased bile salt pool and affected bile salt and phospholipid secretion rates. However, necrosis of zone 3 hepatocytes did not affect bile flow or the bile salt-independent flow, suggesting that hepatocytes of zones 1 and 2 maintained the normal bile salt-independent flow when zone 3 hepatocytes were damaged.

Animals↗

PubMed1990

Cholic acid and chenodeoxycholic acid transport in the hepatic acinus in rats. Effect of necrosis of zone 3 induced by bromobenzene.

The transport of cholic acid (CA) and chenodeoxycholic acid (CDC) and their influence on bile formation was investigated in rats treated with bromobenzene (BZ), a toxicant which selectively destroys zone 3 of the hepatic acinus. The necrosis equals 27-31% of the acinus cells. The absence of zone 3 in rats reduced the secretory rate maximum of CA and CDC by 18% (NS) and 25% (p less than 0.05), respectively. The maximum bile flow was not different from control during CA infusion but was lower during CDC infusion in BZ-treated animals. Although the bile acid concentration was lower in BZ-treated rats, only values obtained during the basal period and the beginning of the infusion reached the level of statistically significant difference. The bile salt-independent flow (BSIF) was not affected by the absence of zone 3. Our data suggest that zones 1 and 2 of the hepatic acinus can compensate for the secretion of CA and elaboration of BSIF when zone 3 is destroyed. However, necrosis of zone 3 reduces CDC secretion. Thus, the capacity for bile acid transport of the hepatocytes of different zones in the hepatic acinus may differ according to the circulating bile acid.

Animals↗