Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morphologically identical liver damage may be caused by dihydralazine (Depressan, Nepresol) and propranolol (Obsidan, Dociton). Among 24 patients with clinical manifestations of drug-induced hepatitis associated with Depressan or Obsidan treatment, liver biopsies in 15 showed drug hepatitic changes with confluent necrosis. In five of these cases this finding was combined with cholangiolitis, in four there was a drug-induced hepatopathy resembling the picture of viral hepatitis. In 20 cases of Ketazon-induced liver damage the biopsy demonstrated toxic hepatosis with or without cholestasis, reactive hepatitis or cholangiolitis. A drug-related hepatitis with central lobular necrosis was observed in one patient with Ketazon-induced liver damage. In 28 patients a lymphocyte proliferation test was undertaken to confirm a causal relationship between the use of either Depressan, Obsidan or Ketazon and the morphologically demonstrated liver damage. The test was positive in 25 cases (18 with Depressan, 2 with Obsidan and 5 with Ketazon). In several uncertain cases, for example, exposure to both Depressan and Obsidan or to Ketazon and Rewodina, the morphologic picture could be attributed to a specific medication by the use of the lymphocyte proliferation test. The results of the lymphocyte proliferation test and the morphologic findings emphasize the role of cell-mediated immune reactions in the pathogenesis of liver damage from dihydralazine, propranolol, and ketophenylbutazone.
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PMID:[Morphology and pathogenesis of liver injury produced by dihydralazine , propranolol and ketophenylbutazone]. 384 42

Dihydralazine-induced hepatitis is characterized by the presence of anti-liver microsomal (anti-LM) autoantibodies in the sera of patients. Cytochrome P450 1A2 (CYP1A2), involved in the metabolism of dihydralazine, was shown to be a target for autoantibodies. In order to investigate further the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, and since the specificity of anti-LM autoantibodies towards CYP1A2 has been determined, the antigenic site was further localized. By constructing fragments derived from CYP1A2 cDNA and probing the corresponding proteins with several anti-LM sera, we were able to define a region (amino acid 335-471) which was immunoreactive with 100% of sera. An internal deletion in this region led to the loss of recognition by anti-LM autoantibodies, confirming that the epitope was conformational. Epitope mapping studies had previously been performed for CYP2D6, CYP17, CYP21A2, and recently for CYP3A1 and CYP2C9. Those data were compared with results obtained in the present study for CYP1A2.
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PMID:Epitope mapping of human CYP1A2 in dihydralazine-induced autoimmune hepatitis. 924 57

Dihydralazine is known to induce immunoallergic hepatitis, and the anti-liver microsome (anti-LM) autoantibodies found in the serum of the patients have been reported to react with cytochrome P450 1A2 (CYP1A2). It is thus suggested that a reactive metabolite of dihydralazine covalently binds to the P450 protein and triggers an immunological response as a neoantigen. We investigated the selectivity of inactivation of P450 enzymes during the metabolism of dihydralazine to evaluate the target protein of its reactive metabolite. Liver microsomes from male Wistar rats were preincubated with dihydralazine in the presence of NADPH, followed by assays of several monooxygenase activities. Preincubation of microsomes of beta-naphthoflavone-treated rats with dihydralazine resulted in time-dependent loss of phenacetin O-deethylase activity (an indicator of CYP1A2 activity), showing inactivation of CYP1A2 during the dihydralazine metabolism. The preincubation with dihydralazine was less effective on ethoxyresorufin O-deethylase activity in microsomes of beta-naphthoflavone-treated rats (CYP1A1) and pentoxyresorufin O-depentylase activity in microsomes of phenobarbital-treated rats (CYP2B). On the other hand, preincubation of microsomes of untreated rats with dihydralazine caused time-dependent loss of testosterone 2alpha-, 16alpha- (CYP2C11), and 6beta- (CYP3A) hydroxylase activities. These results demonstrated that dihydralazine was metabolically activated by CYP1A2, and the chemically reactive metabolite bound to the enzyme itself and inactivated it, as was suggested by the appearance of anti-LM antibodies in dihydralazine-hepatitis, whereas CYP2C and -3A enzymes were also suggested to be the enzymes that activate dihydralazine and lead to the target of the reactive intermediates.
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PMID:Dihydralazine-induced inactivation of cytochrome P450 enzymes in rat liver microsomes. 953 21

Dihydralazine is known to induce immunoallergic hepatitis. Since anti-liver microsome (anti-LM) autoantibodies found in the serum of the patients react with P450 1A2, it is suggested that dihydralazine is biotransformed into a reactive metabolite, which covalently binds to cytochrome P450 1A2 and triggers an immunological response as a neoantigen. We investigated inactivation of P450 enzymes, including P450 1A2, during the metabolism of dihydralazine to evaluate the selectivity of P450 1A2 as a catalyst and a target of dihydralazine. Human liver microsomes or microsomes from lymphoblastoid cells expressing P450 enzymes were preincubated with dihydralazine in the presence of NADPH, followed by an assay of several monooxygenase activities. Preincubation of human liver microsomes with dihydralazine in the presence of NADPH resulted in decreases in phenacetin O-deethylase activity (an indicator of P450 1A2 activity) and testosterone 6beta-hydroxylase activity (P450 3A4), but not in diclofenac 4'-hydroxylase activity (P450 2C9), an indication of inactivation of P450s 1A2 and 3A4 during the dihydralazine metabolism. The inactivation of both of the P450s followed pseudo-first-order kinetics and was saturable with increasing dihydralazine concentrations. Similar time-dependent decreases in the activities were obtained in the case for use in microsomes expressing P450 1A2 and P450 3A4 instead of the human liver microsomes. The data presented here demonstrated that dihydralazine was metabolically activated not only by P450 1A2 but also by P450 3A4, and the chemically reactive metabolite bound to and inactivated the enzyme themselves, suggesting that dihydralazine is a mechanism-based inactivator of P450s 1A2 and 3A4. The data support the postulated covalent binding of a reactive metabolite of dihydralazine to P450 1A2 as a step in the formation of anti-LM antibodies in dihydralazine hepatitis, but it is not the unique factor for determining the specificity of the autoantibodies.
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PMID:Mechanism-based inactivation of cytochrome P450s 1A2 and 3A4 by dihydralazine in human liver microsomes. 1052 81

Anti-cytochrome P450 (CYP)1A2 autoantibodies are found in dihydralazine-induced hepatitis, and CYPs2B and 2C have been shown to follow vesicular flow to the plasma membrane (PM). However, it is unknown whether other CYPs follow this route, whether NADPH-CYP reductase is present on the hepatocyte surface, and whether autoimmune hepatitis-inducing drugs increase PM CYPs. In this study, we determined the transmembrane topology and transport of CYPs1A in rat hepatocytes. In cultured hepatocytes, colchicine and other vesicular transport inhibitors decreased PM CYPs1A assessed by flow cytometry. Colchicine administration also decreased PM CYPs1A in vivo. Pulse chase experiments with [(35)S]methionine showed that only the newly synthesized CYP molecules are transferred to the PM, whereas microsomal CYP1A2 was stably radiolabeled for several hours. In contrast, radiolabeled CYP1A2 reached the PM and disappeared from the PM with half-lives of less than 30 min. Confocal microscopy, biotinylation, and coimmunoprecipitation experiments showed that PM CYPs1A and CYP reductase are present on the cell surface, and that the reductase is closely associated with PM CYPs. Exposure of whole cells to an anti-CYP1A1/2 antibody at 4 degrees C, before five washes and PM preparation, abolished PM CYPs1A-supported monooxygenase activity, indicating that PM CYPs are mostly located on the external surface. Dihydralazine and other CYPs1A inducers increased PM CYPs1A. In conclusion, newly synthesized CYPs1A follow vesicular flow to the outside of the PM, and NADPH-CYP reductase also is located on the hepatocyte surface. Dihydralazine administration increases PM CYP1A2, its autoimmune target.
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PMID:Vesicular transport of newly synthesized cytochromes P4501A to the outside of rat hepatocyte plasma membranes. 1094 60