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 effect of Picroliv on hepatic microsomal mixed-function oxidases (MFO) and glutathione conjugating enzyme system in cholestatic rats was studied. Bile duct ligation in male rats for one weeks caused significant increase in both serum sorbitol dehydrogenase activity and serum bile acide concentration indicating cholestatic liver injury. Furthermore, a rise in the hepatic hydroxyproline level indicating collagen accumulation was observed. As a result of these alterations, the hepatic microsomal MFO system was imparied as evidenced by a decrease in cytochrome P-450 system content and in the activities of NADPH-cytochrome C reductase and aminopyrine demethylase. While the hepatic glutathione content remained unaffected, the cytosolic glutathione S-transferase activity was clearly suppressed due to subchronic cholestasis. Oral administration of Picroliv (25 mg/kg/day for 21 days)--a standardized irioid glycoside fraction of Picrorhiza kurroa in bile ligation induced cholestatic rats, singnificantly prevented the biochemical changes induced in liver and serum of cholestatic rats. These results suggested that picroliv has anti-cholestatic activity which may be attributed to antioxidant property or it's specific role in protein synthesis.
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PMID:Effect of picroliv administration on hepatic microsomal mixed function oxidases and glutathione-conjugating enzyme system in cholestatic rats. 1869 26

Medications inhibiting 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase are commonly used as lipid-lowering therapy. Myopathy has been reported as a rare adverse effect in up to 0.2% of patients; however, this complication appears to be more common in patients who are concurrently receiving cyclosporin A(CsA). We present a case of a 74-year-old woman tolerating a stable dose of simvastatin 80 mg daily for hyperlipidemia. After the addition of CsA for a corneal stem limbal cell transplant, the patient experienced a cholesterol-lowering agent myopathy syndrome (CLAMS), with creatine phosphokinase values up to 78,472 U/L. We explore the interaction between simvastatin and CsA, including effects on hepatic microsomal metabolism via the cytochrome P-450 pathway, cholestasis, and myoblast histology, with a review of previous literature regarding HMG-CoA reductase inhibitors (HMGRIs) and rhabdomyolysis. Caution should be exercised in patients receiving concomitant simvastatin and CsA, and a reduced dose of simvastatin is suggested. Inhibition of HMG-CoA reductase is an accepted therapy for hyperlipidemias. The development of a CLAMS is a known potential adverse effect (1), with an increased incidence during coadministration of lovastatin and CsA, first reported by Norman et al. and East et al. in 1988 (2, 3). The interaction between the HMGRIs and CsA, which leads to this muscle toxicity, appears to be related to altered clearance of the HMGRIs with resultant increased tissue exposure (4). The majority of experience with rhabdomyolysis has been in cardiac and renal transplant patients requiring lovastatin and CsA. Theoretically, however, any of the HMGRIs may predispose a patient requiring CsA to develop myositis. In particular, there is a suggestion of an increased sensitivity of myoblasts to both lovastatin and simvastatin (5). We present a case of rhabdomyolysis in a corneal stem cell transplant patient receiving simvastatin and CsA, with a review of the literature.
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PMID:Rhabdomyolysis in a patient taking simvastatin after addition of cyclosporine therapy. 1907 94

Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O(2) supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca(2+)-dependent ATPase, reduced capability to sequester Ca(2+) within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
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PMID:Biochemical mechanisms in drug-induced liver injury: certainties and doubts. 1984 15


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