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)

1. Cholestasis (bile-duct ligation 24 h before) had no effect on rat liver microsomal protein content, cytochrome P-450 or cytochrome c reductase activity, but depressed aniline hydroxylase activity and aminopyrine demethylase less so. Pretreatment with CCl4 (24 h before) decreased rat liver cytochrome P-450, aniline hydroxylase and aminopyrine demethylase. 2. Halothane, enflurane and methoxyflurane are metabolized via different pathways, resulting in different metabolic elimination rates in our exposure system (methoxyflurane greater than halothane greater than enflurane). Elimination half-lives of the three compounds from the atmosphere of the exposure system were three times longer in CCl4-injured rats; cholestasis had a weaker effect (30-50% increase). 3. Dehalogenation of enflurane, which is the preferred pathway, is affected to the same extent as the cytochrome P-450-dependent hydroxylation of halothane and the O-dealkylation of methoxyflurane.
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PMID:Effects of liver injury and cholestasis on microsomal enzyme activities and metabolism of halothane, enflurane and methoxyflurane in vivo in rats. 729 19

1. Microsomal cytochrome P-450 and peroxisomal fatty acid oxidation was studied in the kidney of rats 7 days after bile duct ligation (BDL) and a comparative study between kidney and liver was done. 2. Only in the liver did cholestasis decrease the cytocrome P-450 content and the peroxisomal fatty acid beta-oxidation, the catalase activity, and the microsomal metabolism of lauric acid and aminopyrine. 3. In contrast, cholestasis did not influence these activities in the kidney. The microsomal and peroxisomal activities studied responded in a coordinate way to cholestasis. 4. These results could suggest the possibility of a cause-and-effect relationship between microsomal cytochrome P-450 and peroxisomal activity.
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PMID:Microsomal and peroxisomal fatty acid oxidation in bile duct ligated rats: a comparative study between liver and kidney. 914 20

The threshold for hepatotoxicity and cholestasis induced by methylene dianiline (DAPM) in rats is between 25 and 75 mg/kg (Bailie et al., Environ. Health Perspect., 124, 25-30, 1993). Our objectives were to determine if a minimally toxic dose of DAPM provided a model system for studies of selective injury to biliary epithelial cells (BEC) in vivo. Thus, we examined the effects of 50 mg DAPM/kg on (1) biliary constituents, (2) liver constituents likely involved in DAPM biotransformation/detoxification, and (3) early morphological and histochemical changes in the liver. Male Sprague Dawley rats had biliary cannulas positioned under pentobarbital anesthesia. After 1 h of control bile collection, rats received 50 mg DAPM/kg po in 35% ethanol or 35% ethanol only. Bile was collected for another 6 h. Histochemical, ultrastructural, and biochemical liver alterations were assessed at 3 h or at 3 and 6 h. DAPM had minimal effects on biliary bile salt and bilirubin excretion over 6 h. Biliary glucose and protein excretion were increased approximately 2-fold starting in Hour 1, while inorganic phosphate excretion was not increased until Hour 2. Biliary glutathione excretion initially increased (Hour 1) but then declined steadily for 5 h. Microsomal cytochrome P-450 activities were transiently decreased at 3 h but had returned to control values by 6 h. Liver glutathione (GSH and GSSG) was not affected by DAPM at 3 or 6 h. Necrosis of intrahepatic bile ducts was severe at 6 h with moderate injury in smaller bile ducts. Ultrastructural alterations were observed in BEC mitochondria and microvilli at 3 h with no apparent alterations in hepatocyte mitochondria or tight junctions between cells. In addition, histochemical staining of liver sections and assays of mitochondrial enzyme activities in vitro at 3 h revealed no loss of mitochondrial function in hepatocytes. These results provide strong evidence for defining DAPM as a selective bile duct toxicant.
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PMID:A minimally toxic dose of methylene dianiline injures biliary epithelial cells in rats. 965 73

Alcohol was administered chronically to female Sprague Dawley rats in a nutritionally adequate totally liquid diet for 28 days. This resulted in hepatic steatosis and lipid peroxidation. Taurine, when co-administered with alcohol, reduced the hepatic steatosis and completely prevented lipid peroxidation. The protective properties of taurine in preventing fatty liver were also demonstrated histologically. Although alcohol was found not to affect the urinary excretion of taurine (a non-invasive marker of liver damage), levels of serum and liver taurine were markedly raised in animals receiving alcohol + taurine compared to animals given taurine alone. The ethanol-inducible form of cytochrome P-450 (CYP2E1) was significantly induced by alcohol; the activity was significantly lower than controls and barely detectable in animals fed the liquid alcohol diet containing taurine. In addition, alcohol significantly increased homocysteine excretion into urine throughout the 28 day period of ethanol administration; however, taurine did not prevent this increase. There was evidence of slight cholestasis in animals treated with alcohol and alcohol + taurine, as indicated by raised serum bile acids and alkaline phosphatase (ALP). The protective effects of taurine were attributed to the potential of bile acids, especially taurine conjugated bile acids (taurocholic acid) to inhibit the activity of some microsomal enzymes (CYP2E1). These in vivo findings demonstrate for the first time that hepatic steatosis and lipid peroxidation, occurring as a result of chronic alcohol consumption, can be ameliorated by administration of taurine to rats.
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PMID:Taurine: protective properties against ethanol-induced hepatic steatosis and lipid peroxidation during chronic ethanol consumption in rats. 987 87

This study aimed to examine whether acetaminophen (AAP), an anti-inflammatory agent producing hepatocellular damages with its overdose, evokes hepatocellular dysfunction through mechanisms involving carbon monoxide (CO) generated by heme oxygenase (HO). In perfused rat livers, CO and bilirubin were determined in venous perfusate and bile samples as indices of heme degradation. Biliary excretion of transportally injected horseradish peroxidase was also determined to assess paracellular junctional permeability and vesicular transport across hepatocytes. AAP at 20 mmol/L induced a transient choleresis, followed by a reduction of bile output. Under these circumstances, the release of CO and bilirubin IXalpha, terminal products of the HO-mediated heme degradation, became 2. 5-fold greater than the control. The rate of CO production appeared stoichiometric to the degradation rate of microsomal cytochrome P-450. Mechanisms for the AAP-induced cholestasis involved an increase in the junctional permeability that coincided with a reduction of vesicular transport across hepatocytes. Clotrimazole, a cytochrome P-450 inhibitor, or zinc protoporphyrin IX, an HO inhibitor, but not copper protoporphyrin IX, which did not inhibit HO, attenuated these AAP-induced changes. Furthermore, administration of CO at concentrations comparable with those induced by AAP elicited a marked elevation of the paracellular junctional permeability concurrent with a reduction of transcellular vesicular transport, mimicking effects of the AAP administration. Thus, CO serves as a putative regulator of hepatocellular function that is overproduced through acute heme degradation during xenobiotic transformation.
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PMID:Carbon monoxide-mediated alterations in paracellular permeability and vesicular transport in acetaminophen-treated perfused rat liver. 1038 52

In the liver, seven days of bile duct ligation (BDL) decreases the cytochrome P-450 content and the UDP-glucuronyl transferase activity. Also, a decrease in the water soluble antioxidant mechanism reflected in the activities of the enzymes superoxide dismutase (SOD), catalase and the glutathione peroxidase (GTPx) was found in the liver but not in the kidney. Despite an increase in the amount of the GSH in the liver, increased lipid peroxidation is produced in the BDL rats, as indicated by the levels of malondialdehyde (MDA). The kidney responded in a different way to cholestasis, decreasing only the UDP-glucuronyl transferase activity and increasing the levels of GSH and MDA. In the red blood cells the activity of the antioxidant enzymes SOD, GTPx and catalase and the content of GSH were not modulated by cholestasis. In conclusion, disturbance of the oxidant-antioxidant balance might be responsible for cholestatic liver injury and impaired renal function in BDL rats.
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PMID:Bile duct ligation and oxidative stress in the rat: effects in liver and kidney. 1105 Jun 82

Cyclosporine A and sirolimus are used alone or in combination as immunosuppressants in organ transplantation. To elucidate hepatic side effects, we examined hepatic mRNA of proteins involved in biliary and hepatocellular transport of drugs, formation of glutathione (GSH) and drug metabolising cytochrome P-450 enzymes (CYPs) in rats treated orally for 2 weeks with cyclosporine A (15 mg/kg/day), sirolimus (0.4 mg/kg/day), their combination (same doses), or vehicle. Liver function tests (alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase and bilirubin) in blood were then analysed as were hepatic mRNA levels of canalicular transport proteins (Mrp2, Bsep, Mdr1b and Mdr2), sinusoidal transport proteins (Ntcp, Oatp1 and Oatp2), GSH related enzymes (gamma-glutamylcysteine synthetase light (GCSlc) and heavy (GCShc) chain subunits and glutathione-S-transferase) and CYPs (CYP3A9, CYP1A2, CYP2E1 and CYP2BI/II). Cyclosporine A caused moderate cholestatic changes in liver enzymes, which was synergistically exacerbated by sirolimus. The data suggest that the underlying mechanisms behind cholestasis were not totally identical in the different treatment regimens. Cholestasis secondary to cyclosporine A could be related to reduction in mRNA expression of GSH synthesising enzymes and Mrp2, leading to reduced protection against oxidative stress and reduced bile acid-independent bile flow. After sirolimus treatment, Mrp2 mRNA was also reduced together with reduced levels of most CYPs and increased Oatp2, possibly leading to accumulation of toxic metabolites in the hepatocytes. The enhanced cholestatic effect of the combination treatment could be related to reduced GSH synthesising enzymes and even more pronounced reduction in Mrp2 mRNA and increase of Oatp2 mRNA.
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PMID:Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (Rapamycin). 1158 84

Inductors of the monooxygenase system benzonal, halonal, and halodif prevented the development of intrahepatic cholestasis induced by a-naphthylisothiocyanate and stimulated detoxifying function of the liver in rats. These agents increased the content of microsomal protein and cytochrome P-450 and accelerated metabolism of types I and II substrates. This was accompanied by a decrease of serum concentrations of total and free bilirubin and activity of liver-specific enzymes. Phenobarbital did not prevent the development of hepatocyte cytolysis.
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PMID:Efficiency of enzyme-inducing agents in rats with intrahepatic cholestasis. 1251

Bile salts take part in an efficient enterohepatic circulation in which most of the secreted bile salts are reclaimed by absorption in the terminal ileum. In the liver, the sodium-dependent taurocholate transporter at the basolateral (sinusoidal) membrane and the bile salt export pump at the canalicular membrane mediate hepatic uptake and hepatobiliary secretion of bile salts. Canalicular secretion is the driving force for the enterohepatic cycling of bile salts and most genetic diseases are caused by defects of canalicular secretion. Impairment of bile flow leads to adaptive changes in the expression of transporter proteins and enzymes of the cytochrome P-450 system involved in the metabolism of cholesterol and bile acids. Bile salts act as ligands for transcription factors. As such, they stimulate or inhibit the transcription of genes encoding transporters and enzymes involved in their own metabolism. Together these changes appear to serve mainly a hepatoprotective function. Progressive familial intrahepatic cholestasis (PFIC) results from mutations in various genes encoding hepatobiliary transport proteins. Mutations in the FIC1 gene cause relapsing or permanent cholestasis. The relapsing type of cholestasis is called benign recurrent intrahepatic cholestasis, the permanent type of cholestasis PFIC type 1. PFIC type 2 results from mutations in the bile salt export pump (BSEP) gene. This is associated with permanent cholestasis since birth. Serum gamma-glutamyltransferase (gamma-GT) activity is low to normal in PFIC types 1 and 2. Bile diversion procedures, causing a decreased bile salt pool, have a beneficial effect in a number of patients with these diseases. However, liver transplantation is often necessary. PFIC type 3 is caused by mutations in the MDR3 gene. MDR3 is a phospholipid translocator in the canalicular membrane. Because of the inability to secrete phospholipids, patients with PFIC type 3 produce bile acid-rich toxic bile that damages the intrahepatic bile ducts. Serum gamma-GT activity is elevated in these patients. Ursodeoxycholic acid therapy is useful for patients with a partial defect. Liver transplantation is a more definitive therapy for these patients.
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PMID:Genetic cholestasis, causes and consequences for hepatobiliary transport. 1470 91

6,8-Dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f]xanthine, a new inductor of the monooxygenase system, inhibited the development of experimental intrahepatic cholestasis induced by alpha-naphthylisothiocyanate in rats. The drug stimulated the detoxicating function of liver, increased the survivability of rats, restored the level of microsomal protein and cytochrome P-450, decreased the cell-average erythrocyte fragility, and reduced the activity of cholestasis markers and the amount of TBA-active products in hepatocytes.
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PMID:[6,8-Dimethyl-2-piperidinomethyl-2,3-dihydrothiazolo[2,3-f]xanthine: a new inductor of the monooxygenase system inhibits experimental intrahepatic cholestasis in rats]. 1550 46


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