Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In single-pass perfused rat liver, the sinusoidal uptake of infused 3H-labelled leukotriene (LT) C4 (10 nmol.l-1) was inhibited by sulfobromophthalein. Inhibition was half-maximal at sulfobromophthalein concentrations of approximately 1.2 mumol.l-1 in the influent perfusate and leukotriene uptake was inhibited by maximally 34%. Sulfobromophthalein (20 mumol.l-1) also decreased the uptake of infused [3H]LTE4 (10 nmol.l-1) by 31%. Indocyanine green (10 mumol.l-1) inhibited the sinusoidal [3H]LTC4 uptake by 19%. Replacement of sodium in the perfusion medium by choline decreased the uptake of infused [3H]LTC4 (10 nmol.l-1) by 56%, but was without effect on the uptake of sulfobromophthalein. The canalicular excretion of LTC4, LTD4 and N-acetyl-LTE4 was inhibited by sulfobromophthalein. In contrast, the proportion of polar omega-oxidation metabolites recovered in bile following the infusion of [3H]LTC4 was increased. Taurocholate, which had no effect on the sinusoidal leukotriene uptake, increased bile flow and also the biliary elimination of the radioactivity taken up. With increasing taurocholate additions, the amount of LTD4 recovered in bile increased at the expense of LTC4. Following the infusion of [3H]LTD4 (10 nmol.l-1), a major biliary metabolite was LTC4 indicating a reconversion of LTD4 to LTC4. In the presence of taurocholate (40 mumol.l-1), however, this reconversion was completely inhibited. The findings suggest the involvement of different transport systems in the sinusoidal uptake of cysteinyl leukotrienes. LTC4 uptake is not affected by bile acids and has a sodium-dependent and a sodium-independent component, the latter probably being shared with organic dyes. Sulfobromophthalein also interferes with the canalicular transport of LTC4, LTD4 and N-acetyl-LTE4, but not with the excretion of omega-oxidized cysteinyl leukotrienes. The data may be relevant for the understanding of hepatic leukotriene processing in conditions like hyperbilirubinemia or cholestasis.
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PMID:Characteristics of sinusoidal uptake and biliary excretion of cysteinyl leukotrienes in perfused rat liver. 216 7

Primidone, phenytoin, or phenytoin and primidone in combination were given to healthy Beagle dogs for 6 months. Serum biochemical changes in dogs given primidone alone or phenytoin and primidone in combination for the entire 6-month test period included increased activities of alanine aminotransferase, alkaline phosphatase (AP), and gamma-glutamyltransferase, and decreased concentrations of albumin and cholesterol. Changes in dogs given phenytoin alone were limited to increased AP activity and decreased albumin concentration. Sulfobromophthalein excretion and conjugated bile acid concentration were within normal limits. All dogs given primidone alone or phenytoin alone remained clinically healthy throughout the treatment period. Three of 8 dogs given both drugs in combination became clinically ill after 9, 14, and 15 weeks of treatment, and were euthanatized. Two of the dogs developed clinical jaundice. In addition to the serum biochemical abnormalities observed in clinically healthy dogs, these dogs developed hyperbilirubinemia, delayed sulfobromophthalein excretion, and increased conjugated bile acid concentrations. Histologic examination of the liver showed intracanalicular casts of bile pigment typical of intrahepatic cholestasis in all 3 dogs. Histologic findings characteristic of treated dogs included hepatocellular hypertrophy attributable to hyperplasia of the smooth endoplasmic reticulum. Single-cell necrosis and multifocal lipidosis were observed in individuals of all treatment groups. Electron microscopy of the liver showed dilated bile canaliculi and damaged sinusoidal epithelium in dogs given both drugs. The elevated serum AP activity, associated with anticonvulsant drug therapy, was found to be exclusively the liver isoenzyme by cellulose acetate electrophoresis. The hepatic AP was localized to primarily the canalicular membranes by enzyme histochemistry. There was a statistically significant positive correlation between the AP activities of liver and serum. The results of this study indicate that long-term administration of anticonvulsant drugs to dogs is associated with clinical, serum biochemical, and histologic evidence of hepatic dysfunction. High drug dosage contributed most to abnormal serum biochemical test results, and combining phenytoin with primidone was responsible for more severe electron microscopic lesions of the liver of surviving dogs and for the death of 3 dogs.
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PMID:Effects of long-term primidone and phenytoin administration on canine hepatic function and morphology. 285 43

Yellow-brown deposits in intrahepatic bile ducts and portal macrophages were observed for male, but not female, Sprague- Dawley rats fed zanoterone, a steroidal antiandrogen, for >=3 months. The lesion did not affect biliary canaliculi and was associated with changes of biliary epithelium, portal chronic inflammation, and bile duct proliferation. Deposit formation was assumed to be related to a gender-related anomaly in bile composition and/or flow. Therefore, the pathogenesis of the lesion was investigated in male, female, and orchiectomized rat. Hepatobiliary structure and function were evaluated after 3 months of treatment and 3 months of reversibility. Drug biliary disposition was evaluated at 3 months. Sulfobromophthalein clearance, bile flow, and plasma concentration and biliary excretion rate of cholesterol were increased at the end of the treatment phase without significant sex-related differences. These effects are consistent with the hepatic enzyme induction potential of the drug, were accompanied by perivenous hepatocellular hypertrophy and increased liver weights, and were no longer observed at the end of the recovery phase. Histomorphologic evidence of cholestasis was observed for most intact and orchiectomized males, the lesion being slightly less pronounced for the latter. Deposits were present at the end of the recovery phase, but were confined to macrophages in all but one case. The lesion differed from a protoporphyria, or precipitates of bile pigments, cholesterol, or proteins. The drug was extensively metabolized with major gender-related differences. Glucuronides of a 16- hydroxy- and another unidentified metabolite were the major metabolites found in bile of males, while a 15-hydroxy-glucuronide was the major metabolite for females. The concentration and biliary excretion of the 16-hydroxy- glucuronide markedly increased after chronic exposure. A possible explanation for pigment deposition in males is that the drug is converted to a metabolite(s) which is excreted at a rate beyond the solubilization potential of bile and, therefore, precipitates in bile ducts.
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PMID:Functional, biochemical, and morphological hepatobiliary effects in rats chronically exposed to a steroidal antiandrogen. 860 38

Estradiol-17beta-glucuronide (E217G) is a cholestatic agent and is considered to be related to the pathogenesis of intrahepatic cholestasis of pregnancy. In the current study, we examined the mechanism of the biliary excretion of E217G and estradiol metabolites in rats. Biliary excretion of tracer doses of [3H]estradiol-17beta-glucuronide and [14C]estradiol or [3H]taurocholate and ]14C]vinblastine, a P-glycoprotein (P-GP) substrate, intravenously administered as a bolus to bile-drained control rats or EHBR was studied. Biliary excretion of E217G and estradiol metabolites EHBR was markedly delayed. Analyses of biliary metabolites after estradiol injection showed less polar conjugates in EHBR. In contrast, the excretion of taurocholate and vinblastine (VLB) was only slightly delayed in EHBR. Although phenothiazine treatment to induce the expression of P-GP increased biliary vinblastine excretion, it did not affect biliary excretion of a tracer dose of [3H]estradiol-17beta-glucuronide. However, phenothiazine treatment inhibited the cholestasis induced by E217G infused at the rate of 0.075 micromol/min/100g for 20 minutes and increased biliary E217G excretion. Sulfobromophthalein infusion (0.2 micromol/min/100 g body 0 weight) markedly inhibited the biliary excretion of E217G and estradiol metabolites, whereas dibromosulfophthalein (DBSP) at the same infusion rate had no effect. These findings indicate that EG17G is excreted into bile by a canalicular organic anion carrier for sulfobromopthalein (BSP), not for DBSP, under physiological conditions, and that P-GP influences E217G excretion only at a high dose. under physiological conditions, and that P-GP influence s E217G excretion only at a high dose.
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PMID:Biliary excretion of estradiol-17 beta-glucuronide in the rat. 861 43

The aim of this investigation was to reproduce in rats a partial stenosis of the common bile duct to analyze early liver functional and morphometric changes. The hepatic transport kinetics of sulfobromophthalein (organic anion) and rhodamine B (organic cation) was also investigated, and compartmental analysis of both compounds was performed. The humoral parameters of liver function indicated a cholestasis after 2 days of surgery, which reverted to reach normal values on the seventh day. Tumor necrosis factor alpha serum levels showed a tendency to increase on the second day of stenosis (7 out of 14 rats) while white blood cells increased on the second day of stenosis, and turned to normal levels on the seventh day. Histological studies showed increased volume of portal areas and ductular proliferation, which did no revert during the time of the study (up to 7 days post-op). Conversely, a moderate fibrosis and leukocyte infiltrates in portal areas predominated on the second day of stenosis, but normalized on the seventh day. Bile flow was considerably diminished on the second day of partial obstruction as compared to controls. The mean recovery in bile of sulfobromophthalein after 1h of being injected was low on the second day of stenosis, but normalized on the seventh day. Conversely, that of rhodamine B was very low in all animals. Sulfobromophthalein kinetics showed that hepatic uptake and canalicular excretion were impaired during the second but normalized on the seventh day of stenosis. However, rhodamine B kinetics showed that this compound was poorly excreted in all groups although canalicular excretion increased on the second day. The results suggested a model of obstructive cholestasis induced by the experimental stenosis of the bile duct which was not only reversible but also implicates the role of hepatic inflammation.
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PMID:Reversible cholestasis induced by experimental partial obstruction of the bile duct; Biochemical, morphometric and hepatic transport kinetic studies. 1517 10