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)

A single i.p. dose of 20 mg/kg of carmustine [1,3-bis-(2-chloroethyl)-1-nitrosourea; BCNU] caused intrahepatic cholestasis in rats within 48 hr of administration. Cholestasis was characterized by a selective reduction of the bile salt independent fraction of bile flow. Increased plasma K+ and decreased plasma Na+ concentrations, consistent with this effect, were observed. Because bile: plasma osmolality and biliary bile salt concentrations were elevated, increased permeability to bile salts and other osmotically active solutes between bile and plasma is unlikely. Bile salt excretion was normal despite the reduced bile flow because biliary bile salt concentration was increased. In contrast, the treated rats were unable to concentrate bromosulfophthalein in bile before, during and after the onset of cholestasis. Because no reduction in hepatic perfusion was observed in vivo in BCNU-treated rats, reduced xenobiotic organic anion excretion may be a selective effect of the drug. The cholestatic effects of BCNU appear to be different from either alpha-naphthylisothiocyanate or estrogenic steroids.
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PMID:Cholestatic effect of carmustine in rats. 254 Mar 12

Biotransformation of xenobiotics is a life saving function of the liver. As a consequence of the tremendous development of new and highly effective drugs this function is frequently overburden. In recent years the number of patients with pharmocotoxic liver damage has become greater than that of patients with viral hepatitis. The liver answers xenobiotic overcharge by a limited spectrum of functional, morphological and clinical reaction patterns that can be caused also by other noxious agents. The manifestation of liver damage depends on a variety of factors such as properties of the drug, mode of administration, reactivity of the whole organism and of the liver as the target organ. From the clinical point of view, xenobiotics can be divided into compounds with foreseeable liver damage and into others in which liver damage is not foreseeable as well as into drugs which produce mainly cholestasis and others in which hepatitis dominates. Mixed patterns are possible. For clarifying diagnostic, differential diagnostic and therapeutic problems a graduated program is proposed. Prophylactic measures are based on this program. The increase of pharmacotoxic damage of the liver and other organs and the expected development leads to consequences and recommendations in health care.
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PMID:[Drug-induced liver damage from a clinical viewpoint]. 383 8

To determine whether cytochrome P450 proteins were differentially altered in severe chronic liver diseases, we examined 50 livers removed at liver transplantation from patients with end-stage cirrhosis, including 18 with and 32 without cholestasis, and compared the results with 21 histologically normal livers. NADPH-cytochrome c reductase activities were unaltered in microsomes from cirrhotic livers. Total cytochrome P450 content was significantly reduced. The catalytic activities of four xenobiotic-metabolizing P450s and the level of the corresponding proteins were differentially altered. Thus, P450 3A-supported testosterone 6 beta-hydroxylase activity and 3A protein appeared to be reduced, but only in the subgroup without cholestasis was this change significant. In contrast, 2E1 and the related N,N-dimethylnitrosamine N-demethylase activity were clearly reduced in livers from patients with cholestatic forms of cirrhosis but appeared not to be changed in other cirrhotic livers. Similarly, P450 2C protein was reduced only in patients with severe chronic cholestasis. Finally, P450 1A2 and 1A2-supported ethoxyresorufin O-deethylase activity were significantly reduced in hepatic microsomes from patients with both types of advanced liver disease. In summary, these data demonstrate that cytochrome P450 proteins are selectively altered in severe chronic liver disease, some being profoundly decreased, others less so or not at all. Our results also suggest that there may be different patterns of altered hepatic P450 expression according to the presence or absence of cholestasis in patients with cirrhosis severe enough to require transplantation.
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PMID:Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. 780 44

P-glycoprotein, an energy-dependent plasma membrane drug-efflux pump capable of reducing the intracellular concentration of a variety of hydrophobic xenobiotics, is encoded by mdr1, a member of the multidrug-resistant (mdr) gene family. The physiological function of this protein is unknown. Because of its location on the bile canalicular domain of the hepatocyte, we and others have hypothesized that P-glycoprotein may have a physiological role as a biliary transporter of xenobiotics and endobiotics and that its expression may therefore be altered in cholestasis. Both obstructive and alpha-naphthylisothiocyanate-induced cholestasis increased mdr1a and 1b gene expression in rat liver. Hepatic P-glycoprotein levels were also increased, and the protein remained localized at the biliary hepatocyte domain. Induction of mdr1a and mdr1b gene expression in rat liver was accomplished by means of increased transcription. alpha-Naphthylisothiocyanate-induced cholestasis in cynomolgus monkeys increased hepatic expression of both the mdr1 and 2 genes. To investigate the possible role of P-glycoprotein as a biliary efflux transporter, biliary excretion of vinblastine, a representative substrate of P-glycoprotein, was studied in rats. Increased hepatic mdr messenger RNA and P-glycoprotein levels, mediated by the xenobiotic inducer 2-acetylaminofluorene, resulted in a significant increase in biliary excretion of vinblastine, which was antagonized by the P-glycoprotein inhibitor verapamil. These findings suggest that P-glycoprotein functions as a biliary efflux pump for xenobiotics and, possibly, for unidentified physiological inducers that may mediate increased transcription of the mdr gene observed during cholestasis.
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PMID:Induction of multidrug resistance gene expression during cholestasis in rats and nonhuman primates. 809 15

Human placental xenobiotic metabolizing and aromatase activities were measured in placentae at term obtained from pregnancies diagnosed as intrahepatic cholestasis (IC). Compared with controls, several cytochrome P450-dependent (CYP) mono-oxygenases were significantly decreased in IC placentae: 7-ethoxycoumarin O-deethylase by 75 per cent, 7-ethoxyresorufin O-deethylase by 95 per cent, aromatase activity by 37 per cent and androstenedione formation, using testosterone as a substrate, by 20 per cent. These results demonstrate that maternal intrahepatic cholestasis effectively decreases CYP dependent metabolism in human placenta in vitro which may pose a potential risk to the wellbeing of the fetus. Because aromatase activity in IC placentae is significantly lower as compared with healthy controls, safety of the drug therapies which further inhibit aromatase activity are questioned.
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PMID:Intrahepatic cholestasis of pregnancy impairs the activities of human placental xenobiotic and steroid metabolizing enzymes in vitro. 903 8

The liver converts endogenous and xenobiotic lipophilic compounds into anionic conjugates with glutathione, glucuronate, or sulfate. These conjugates are transported across the canalicular (apical) membrane into bile by a 190 kDa membrane glycoprotein that has been cloned recently. This apical conjugate-transporting ATPase has been termed canalicular multidrug resistance protein (cMRP) because of the similarity in substrate specificity and sequence with the multidrug resistance protein (MRP1), canalicular multispecific organic anion transporter (cMOAT), or multidrug resistance protein 2 (MRP2). The amino acid sequence identity of human MRP2 and MRP1 is 49%. MRP2 is predominantly expressed in hepatocytes and localized to apical membrane domains. MRP2 is not expressed in the human Dubin-Johnson syndrome, which is therefore associated with an inherited deficiency in the secretion of amphiphilic anionic conjugates into the bile. The rat homolog Mrp2 is absent in two mutant strains of rats with different point mutations in the corresponding gene. These mutant rats are hyperbilirubinemic and deficient in the ATP-dependent transport of conjugates from hepatocytes into bile. Impairment of bile flow (cholestasis) can be associated with a down-regulation of the expression of the conjugate export pump, and MRP2 contributes to bile flow as an important driving force.
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PMID:Hepatic canalicular membrane 5: Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. 921 74

Optimal management of chronic liver disease requires an understanding of aetiological factors or conditions initiating and sustaining tissue damage. Injury may derive initially from toxin or xenobiotic exposure (direct, biotransformation adducts, hypersensitivity responses or immune-mediated mechanisms), infectious organisms, inborn errors of metabolism, or pathological accumulations of transition metals (iron or copper), endotoxins or membranocytolytic bile acids. Secondarily, cells and mediators associated with inflammation, pathological expression of major histocompatibility foci on hepatocytes and biliary epithelia, aberrant initiation of apoptosis, modification of the extracellular matrix, and depletion of natural antioxidants can each play pivotal roles. Cholestatic liver injury derived from extrahepatic mechanical obstruction or intrahepatic cholestasis (many causes) can induce membrane damage subsequent to accumulation of membranocytolytic bile acids, copper retention, and membrane peroxidation. This paper reviews contemporary issues of chronic hepatocellular injury and hepatic fibrosis with the aim of broadening the clinical perspective of treatment strategies.
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PMID:Chronic liver disease: current concepts of disease mechanisms. 1020 Sep 20

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

Hepatic hydroxylation is an essential step in the metabolism and excretion of bile acids and is necessary to avoid pathologic conditions such as cholestasis and liver damage. In this report, we demonstrate that the human xenobiotic receptor SXR (steroid and xenobiotic receptor) and its rodent homolog PXR (pregnane X receptor) serve as functional bile acid receptors in both cultured cells and animals. In particular, the secondary bile acid derivative lithocholic acid (LCA) is highly hepatotoxic and, as we show here, a metabolic substrate for CYP3A hydroxylation. By using combinations of knockout and transgenic animals, we show that activation of SXR/PXR is necessary and sufficient to both induce CYP3A enzymes and confer resistance to toxicity by LCA, as well as other xenotoxicants such as tribromoethanol and zoxazolamine. Therefore, we establish SXR and PXR as bile acid receptors and a role for the xenobiotic response in the detoxification of bile acids.
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PMID:An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. 1124 86

Cholestasis is associated with accumulation of bile acids and lipids, and liver injury. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic nuclear receptors that coordinate protective hepatic responses to potentially toxic stimuli, including bile acids. We investigated the role of these receptors in the regulation of bile acid and lipid metabolism in a bile duct ligation (BDL) model of cholestasis applied to receptor knockout mice. Hepatic damage from bile acid accumulation was increased in both CAR knockout (CARKO) and PXR knockout mice, but bile acid concentrations were lower in CARKO mice. High-density lipoprotein (HDL) cholesterol was elevated in CARKO mice, and serum total cholesterol increased less in CARKO or PXR knockout mice than WT mice after BDL. Gene expression analysis of the BDL knockout animals demonstrated that, in response to cholestasis, PXR and CAR both repressed and induced the specific hepatic membrane transporters Oatp-c (organic anion transporting polypeptide C) and Oatp2 (Na+-dependent organic anion transporter 2), respectively. Induction of the xenobiotic transporter multidrug resistance protein 1 in cholestasis was independent of either PXR or CAR, in contrast to the known pattern of induction of multidrug resistance protein 1 by xenobiotics. These results demonstrate that CAR and PXR influence cholesterol metabolism and bile acid synthesis, as well as multiple detoxification pathways, and suggest their potential role as therapeutic targets for the treatment of cholestasis and lipid disorders.
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PMID:Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury. 1568 63


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