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)

The effects of biliary obstruction and drainage on the hepatic microsomal mixed function oxidase system were studied in rats. Bile duct obstruction produced a significant reduction in the hepatic cytochrome P-450 dependent mixed function oxidase system. After release of the bile duct obstruction, the reduction in microsomal enzymes was practically reversible; however, the process of recovery was slow and differed with the microsomal enzymes in question. Increases in cytochrome b5 content and NADH-cytochrome b5 reductase activity were slower than increases in cytochrome P-450 content and NADPH-cytochrome c reductase activity. Aniline hydroxylase activity increased more rapidly and corresponded to cytochrome P-450 contents more so than did the aminopyrine demethylase activity. After the release of bile duct obstruction, however, the bile acids which had accumulated in the liver during cholestasis were reduced rapidly, to a normal range. These results suggests that there is a discrepancy between reductions in hepatic bile acids and those in the hepatic microsomal mixed function oxidase system after biliary decompression.
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PMID:Effects of bile duct obstruction and decompression on hepatic microsomal mixed function oxidase system in rats. 313 3

Liver tumors are induced in male Syrian golden hamsters by the combined treatment with diethylstilbestrol (DES) and 7,8-benzoflavone (7,8-BF), but not with either substance alone. With the aim of clarifying whether metabolic activation of DES is involved in the mechanism of tumorigenesis in this animal model, we have studied the effect of pretreatment with 7,8-BF alone, DES alone, and 7,8-BF plus DES for 2, 8, 20 and 32 weeks on the hepatic in vivo metabolism of DES, using biliary metabolites collected from bile-duct cannulated male hamsters as probe. Formation of glucuronides and sulfates was not affected by treatment with 7,8-BF nor 7,8-BF plus DES. In contrast, animals pretreated with DES alone had a decreased amount of glucuronides and an increased proportion of unconjugated material in the bile. Oxidative metabolism of DES was not significantly altered in hamsters treated with 7,8-BF for up to 20 weeks, whereas pretreatment with DES alone and with 7,8-BF plus DES caused an enhancement of oxidative DES metabolism in vivo, leading mostly to highly polar, as yet unidentified products. From a consideration of various cytochrome P-450-associated enzyme activities, it is concluded that the observed effect on biliary DES metabolites is most likely to be due to an estrogen-induced intrahepatic cholestasis. Taken together, the data do not support a role for the metabolic activation of DES in this tumor model. Alternative mechanisms are proposed.
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PMID:Effect of pretreatment with 7,8-benzoflavone and diethylstilbestrol on the hepatic metabolism of diethylstilbestrol in the male Syrian golden hamster in vivo. 317 71

The elimination of caffeine from plasma and the excretion of the main metabolites of metamizol (noramidopyrinemethanesulphonate sodium) into the urine were determined in healthy pregnant women (weeks 30-38 of pregnancy) and in patients with intrahepatic cholestasis in pregnancy (weeks 28-39 of pregnancy). From the elimination velocity of these model substances conclusions concerning the activity of 3-methylcholanthrene (caffeine elimination) and phenobarbital inducible isoenzymes (metamizol elimination) of cytochrome P-450 are drawn. Patients with intrahepatic cholestasis in pregnancy (t1/2 = 15.8 +/- 1.8 h) eliminate caffeine more slowly than healthy pregnant women (t1/2 = 11.0 +/- 0.8 h) at this stage of pregnancy. The excretion of the metabolites of metamizol is only in tendency diminished in patients with intrahepatic cholestasis. The influence of the intrahepatic cholestasis on the cytochrome P-450 isoenzymes investigated differs in degree.
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PMID:[The effect of intrahepatic cholestasis in pregnancy on various forms of cytochrome P-450-dependent biotransformation reactions]. 367 45

The possibility of a relationship between hepatic and renal cytochrome P-450 contents was assessed in rats with liver disease. In rats killed 3 days after two-thirds hepatectomy (a model for hepatocellular insufficiency), the total microsomal cytochrome P-450 content of the whole liver was decreased by 60% as compared to that in control rats; renal cytochrome P-450 was increased by 30% while the 7-ethoxycoumarin deethylase activity of kidney microsomes was increased by 80%. In rats killed 7 days after bile duct ligation (a model for cholestasis) or 35 days after bile duct ligation (a model for biliary cirrhosis), hepatic cytochrome P-450 was decreased by 60% and 45%, respectively, while renal cytochrome P-450 content was increased by 50% and 150%, respectively. In contrast, in rats killed 15 days after the last dose of carbon tetrachloride, 1.3 ml/kg twice weekly for 3 months (a model for post-necrotic cirrhosis), both hepatic and renal cytochrome P-450 contents remained unchanged. Phenobarbital (80 mg/kg daily for 3 days) was a poor inducer of renal cytochrome P-450 in sham-operated rats but became a potent inducer of renal cytochrome P-450 in rats with two-thirds hepatectomy. We conclude that renal cytochrome P-450 is increased in three models in which hepatic cytochrome P-450 contents are decreased (two-thirds hepatectomy, cholestasis and biliary cirrhosis), but remains unchanged in a model of severe liver pathology, in which hepatic cytochrome P-450 content is not modified (late, post-necrotic cirrhosis). The hypothetical role of endogenous inducer(s) is discussed.
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PMID:Regulation of renal cytochrome P-450. Effects of two-thirds hepatectomy, cholestasis, biliary cirrhosis and post-necrotic cirrhosis on hepatic and renal microsomal enzymes. 391 37

Bile duct ligation in male rats for two weeks led to a marked increase in both serum sorbitol dehydrogenase activity and serum bile acid concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a consequence of these alterations, the hepatic microsomal mixed-function oxidase system was impaired as evidenced by a decrease in cytochrome P-450 content and in the activities of NADPH-cytochrome c reductase and aminopyrine-demethylase. While the hepatic glutathione content remained unaffected, the cytosolic GSH S-transferase activity was clearly suppressed due to subchronic cholestasis.
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PMID:Effect of subchronic cholestasis on microsomal mixed-function oxidases and the glutathione-conjugating enzyme system in rat liver. 405 19

Investigations in guinea pigs to evaluate interferences between cholestasis and enzymatic induction by phenobarbital, and influences that both experimental conditions exert on the levels of gamma-glutamyl transpeptidase in microsomes and other subcellular fractions, have shown that: 1) cholestasis inhibits inductions of cytochrome P-450 from phenobarbital; 2) gamma-glutamyl transpeptidase is not an inducible enzyme in guinea pig; 3) rises or ferum gamma-glutanyl transpeptidase produced either by cholestasis or phenobarbital administration, are not related to an increased enzymatic synthesis in the various subcellular fractions of liver cell.
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PMID:[Influence of cholestasis on enzymatic induction with phenobarbital and other enzymatic aspects: experimental studies on guinea pigs]. 415 99

In rats, troleandomycin induces microsomal enzymes and promotes its own transformation into a metabolite forming an inactive complex with the iron (II) of cytochrome P-450; eventually, several monooxygenase activities are markedly reduced. In humans, troleandomycin also induces microsomal enzymes, and forms an inactive cytochrome P-450-troleandomycin metabolite complex; the clearance of antipyrine, that of theophylline, and that of methylprednisolone are markedly reduced. The concomitant administration of troleandomycin and other drugs may produce ischaemic accidents (ergotamine), cholestasis (oral contraceptives) and neurologic signs of intoxication (theophylline or carbamazepine). Qualitatively similar effects are produced, in rats and in humans, by erythromycin. These effects, however, are much weaker than those of troleandomycin. In humans, the clearance of antipyrine and that of theophylline are only slightly affected. Drug interactions have been reported in a few patients only. Josamycin and midecamycin do not form cytochrome P-450-metabolite complexes in rats. In humans, these macrolides do not inhibit the clearance of theophylline; midecamycin does not inhibit the clearance of antipyrine. Although a case of possible josamycin-ergotamine interaction has been reported, the role of josamycin may be questioned in this isolated instance. Midecamycin, or josamycin, might be preferred to other macrolides in those patients who must receive other drugs metabolized by cytochrome P-450.
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PMID:Effects of macrolide antibiotics on drug metabolism in rats and in humans. 638 41

Administration of 2.5% griseofulvin in the diet to male CD1 mice produced protoporphyria and cholestasis. Protoporphyria became evident as early as after 10 days of treatment, whereas cholestasis, expressed in terms of total bile flow reduction, developed only after 45 days of griseofulvin. Bile flow impairment was due both to the length of treatment and to the severity of liver protoporphyria. Griseofulvin administration was also associated with a significant modification of the relative amounts of hepatic microsomal cytochromes P-450 and b5, a loss in concentration/mg of protein of cytochrome P-450 and a concomitant increase of b5. Despite these changes, the activity of aniline hydroxylase expressed per mg of microsomal protein, assessed in vitro, was not modified.
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PMID:Bile secretion and liver microsomal mixed function oxidase system in mice with griseofulvin-induced hepatic protoporphyria. 667 36

Concurrent treatments of cobalt chloride (CoCl2) and phenobarbital (PB), alone or in combination with lithocholic acid (LCA), were administered to rats for 7 days to assess whether or not a hypoactive hypertrophic smooth endoplasmic reticulum (HHSER) could be induced, as well as investigating the potential role of HHSER in the pathogenesis of cholestasis. LCA given alone slightly reduced hepatic triglycerides, significantly elevated plasma triglycerides and decreased microsomal glucose-6-phosphatase (G6P-ase) activity. PB administered alone significantly increased hepatic phospholipids and microsomal protein, phospholipid and cytochrome P-450 contents, as well as microsomal aminopyrine-N-demethylase (APDM-ase) activity. Functional indicators of liver impairment were associated primarily with CoCl2 treatment, whether given alone or in combination with PB + LCA. These signs included significantly reduced hepatic triglycerides, and increased plasma triglycerides associated with enhanced release of hepatic VLDL-triglycerides, as well as significantly decreased microsomal G6P-ase activity and/or reduced APDM-ase activity and cytochrome P-450 content. Elevated plasma bilirubin levels, and aspartate and alanine aminotransferase activities were also evident with concurrent CoCl2 + PB + LCA treatments. Combined CoCl2 + PB treatments, with or without LCA, caused significant increases in microsomal protein and phospholipid, and decreased activity of the rough endoplasmic reticulum (RER) marker G6P-ase, but no changes in cytochrome P-450 levels and no marked alterations in the activity of the SER marker APDM-ase. The data indicated that simultaneous CoCl2 and PB treatments, whether given alone or in combination with LCA, caused a functional impairment of the RER, and did not induce HHSER membranes.
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PMID:Functional responses of the rat hepatic endoplasmic reticulum to treatment proposed as a model for cholestasis. 668 66

In order to clarify the mechanism of alpha-naphthylisothiocyanate (ANIT) induced cholestasis in rats, a few hepatic changes seen after administration of ANIT 80 mg/kg body weight were examined in relation to time. To clarify changes in the bile production system and bile flow, the concentrations of bile acid and bicarbonate, as well as of sodium in the bile, were measured after infusion of secretin and taurocholic acid. The canalicular bile flow was estimated by measuring the biliary clearance of erythritol-C14. To assess hepatocellular injury, the levels of cytochrome P-450 in the microsome of hepatocytes and protein synthesis in the liver were estimated. It seems that ANIT is activated in the drug metabolising system through cytochrome P-450 in the liver, and significant changes are produced in both the bile acid metabolism and its transport system. Bile acid-independent bile flow in the canaliculus was inhibited, too. Hence, both the bile ductules and the bile ducts are functionally and histologically disturbed.
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PMID:Studies of alpha-napthylisothiocyanate-induced hepatic disturbance. 720 78


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