UMLS:C0019158 - FACTA Search

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Query: UMLS:C0019158 (hepatitis)
30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A mutant strain of LEC rats (Long-Evans rats with a cinnamon-like coat color) develop spontaneous hepatic injury associated with severe jaundice about 4 months after birth. Recently, we obtained evidence which shows an unusual accumulation of copper (Cu) in the liver of LEC rats, followed by the finding of copper-metallothionein (Cu-MT) induction. To know the mechanism for the development of hepatitis in LEC rats, in relation to induced Cu-MT, we examined whether the generation of active oxygen species is observed. When the Cu-MT was treated with H2O2, which is formed by dismutation of superoxide anion radicals or NADPH oxidases in living systems, strong ESR signals due to Cu(II) state appeared when measured at 77K. On the same system, ESR signals due to the spin trapped hydroxyl radicals were observed at room temperature when DMPO (5,5-dimethyl-pyrroline-1-oxide) was used as a spin-trapping agent. The present results suggested that Cu-MT of LEC rat has an important pathogenic role by generating hydroxyl radicals, when hydrogen peroxide is produced in cells or tissues.
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PMID:Unusual generation of hydroxyl radicals in hepatic copper-metallothionein of LEC (Long-Evans cinnamon) rats in the presence of hydrogen peroxide. 812 29

The effect of Gomisi (dried ripe fruit of schizandra chinensis) on chlorodifluoroethylene (CDE) and chlorotrifluoroethane (CTE) formation was investigated. The incubation mixtures for the measurement of reductive metabolites of halothane consisted of liver microsomal suspensions, 3 mM NADPH, extract solution of Gomisi and halothane in 0.1 M potassium phosphate buffer (pH 7.4). The production of CDE and CTE was inhibited by Gomisi in a dose-dependent way. The production were reduced to half in the presence of 0.5% Gomisi extract in the reaction mixture. The results suggest that Gomisi can inhibit the reductive metabolism of halothane in vitro; thus it may protect against halothane-induced hepatitis.
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PMID:Inhibitory effect of gomisi on reductive metabolism of halothane. 828 41

It has been reported that cytochrome P450 is expressed in the plasma membrane of hepatocytes isolated from human and rat. Cytochrome P450s expressed on the cell surface are potential targets for the immune response of drug-induced and autoimmune hepatitis. However, the mechanisms behind transport of cytochrome P450 to the plasma membrane are obscure. The present investigation aimed at identifying cytochrome P450 expressed in the Golgi apparatus. Golgi membrane fractions from rat liver were prepared and characterized: one enriched with cis-Golgi, one highly enriched with trans-Golgi, and one intermediate Golgi fraction representing medial-Golgi. In these three fractions, significant amounts of cytochrome P450 and NADPH cytochrome P450 reductase were present, which could not be accounted for by contamination with endoplasmic reticulum. A marked difference between the relative content of different cytochrome P450 enzymes was found. CYP4A1 was found at the highest concentration, CYP2E1 at an intermediary level, and CYP1A2 at low levels, whereas no Golgi-specific CYP3A1 was detectable. It was also shown that the CYP2E1 present in the Golgi fractions was catalytically active. It is suggested that various forms of hepatic cytochrome P450 are transported to the plasma membrane through the Golgi apparatus in an enzyme-specific manner.
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PMID:Enzyme-specific transport of rat liver cytochrome P450 to the Golgi apparatus. 880 87

We found that NADPH-dependent ubiquinone reductase (NADPH-UQ reductase) in rat liver cytosol reduces ubiquinone (UQ) to ubiquinol (UQH2) in lipid membranes and consequently inhibits lipid peroxidation [Takahashi T., et al., Biochem. J., 309, 883-890 (1995)]. Here we examined whether or not this UQH2-regenerating system functions as a cellular antioxidant defense in animals. Rats were given UQ-10 for 2 weeks, and were then exposed to carbon tetrachloride (CCl4). The UQ-10 supplement increased only in the NADPH-UQ reductase and the UQH2-10 pool of rat liver without any appreciable change in the levels of other antioxidant factors. On the other hand, CCl4 markedly increased plasma aspartate aminotransferase and alanine aminotransferase, liver weight and thiobarbituric acid reacting substances formation, which are indicators of CCl4-hepatitis, and it decreased the liver levels of L-ascorbic acid, reduced form of glutathione (GSH), alpha-tocopherol, NADPH-UQ reductase and glutathione S-transferase. However, all the above indicators of CCl4-induced hepatitis were significantly improved in rats given UQ-10. Furthermore, alpha-tocopherol, but neither L-ascorbic acid nor GSH, was significantly saved. UQ-10 supplement also was recovered glutathione S-transferase and NADPH-UQ reductase activities slightly. These results indicated that UQ-10 given to rats increased the cellular UQH2-10 pool and cytosolic NADPH-UQ reductase activity in their livers, resulting in the inhibition of lipid peroxidation in the biomembranes, and consequently protected the rats from the CCl4-hepatotoxicity.
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PMID:Cellular antioxidant defense by a ubiquinol-regenerating system coupled with cytosolic NADPH-dependent ubiquinone reductase: protective effect against carbon tetrachloride-induced hepatotoxicity in the rat. 887 5

Activation of halothane to trifluoroacetyl halide, followed by covalent binding to proteins (neoantigen formation) has been proposed to be the mechanism by which halothane causes immune hepatitis. The aim of this study was to identify the cytochrome P450 (CYP) enzyme primarily responsible for the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes. Human liver microsomes were incubated in the absence and presence of NADPH with various concentrations of halothane (from 4.6 to 3,300 microM) to examine the effects of substrate concentration on the nonspecific and specific (NADPH-dependent) binding of [14C]halothane to microsomal protein. As a function of substrate concentration, the specific binding of [14C]halothane to human liver microsomes was biphasic, suggesting that the activation of halothane is catalyzed by a high-affinity enzyme(s) at low substrate concentrations (<150 microM) and by a low-affinity enzyme(s) at high substrate concentrations (>150 microM). For the high-affinity enzyme, the apparent KM for the covalent binding of [14C]halothane was approximately 10 microM, and Vmax was approximately 32 pmol equivalents of halothane bound/mg protein/min under conditions where covalent binding was directly proportional to incubation time and protein concentration. Ten individual samples of human liver microsomes were incubated with a low concentration of halothane (35 microM) to determine the sample-to-sample variation in the specific binding of [14C]halothane to microsomal protein. Covalent binding ranged from 10 to 40 pmol equivalents of halothane bound/mg protein/min and was highly correlated (r2 = 0.93) with the sample-to-sample variation in chlorzoxazone 6-hydroxylase activity, which reflects the levels of CYP2E1. These results suggest that CYP2E1 is the high-affinity enzyme in human liver microsomes responsible for activating halothane to a reactive metabolite. This is supported by the observation that 4-methylpyrazole, a CYP2E1 inhibitor, inhibited the NADPH-dependent binding of [14C]halothane to microsomal protein. The sample-to-sample variation in the covalent binding of [14C]halothane at high substrate concentrations did not correlate with any known CYP enzyme activity. This suggests that several enzymes catalyze the oxidation of halothane at higher substrate concentrations. In conclusion, at pharmacologically relevant concentrations, the covalent binding of halothane to human liver microsomes is primarily catalyzed by CYP2E1.
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PMID:Characterization of the NADPH-dependent covalent binding of [14C]halothane to human liver microsomes: a role for cytochrome P4502E1 at low substrate concentrations. 897 Nov 35

To confirm whether or not cytosolic NADPH-UQ reductase is involved in the recycling of cellular ubiquinol (UQH2) consumed during lipid peroxidation, the effect of a UQ-10 supplement on the NADPH-UQ reductase and cellular defense against oxidative damage in rat livers was investigated. Supplements of UQ-10 for 14 days enhanced the levels of UQH2-10 and NADPH-UQ reductase in rat livers without any appreciable changes in other antioxidant contents and related enzyme activities. However, the injection of carbon tetrachloride (CCl4) into the rats induced lipid peroxidation and decreased the cellular UQH2-10 contents (and increased equivalent amounts of UQ-10), as well as decreasing the ascorbic acid, reduced glutathione (GSH) and alpha-tocopherol contents of the rat livers. Administration of the UQ-10 supplement prior to the CCl4 treatment spared alpha-tocopherol (but not GSH or ascorbic acid), inhibited lipid peroxidation, and thus improved CCl4-induced hepatitis. These findings support the notion that NADPH-UQ reductase in cytosol is the enzyme responsible for the regeneration of UQH2 from UQ formed by lipid peroxidation in cells.
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PMID:Cytosolic NADPH-UQ reductase-linked recycling of cellular ubiquinol: its protective effect against carbon tetrachloride hepatotoxicity in rat. 926 8

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

The Long-Evans Cinnamon (LEC) rat is a mutant strain of rats that accumulate copper (Cu) in the liver in much the same way as individuals who suffer from Wilson's disease (WD) and has been suggested as a model for this disease. Lipid peroxidation (LPO) is considered to be involved in the toxic action of Cu in the livers of LEC rats. We investigated the mechanism of LPO in the livers of LEC rats showing apparent signs of hepatitis. Several-fold higher LPO levels were observed in post-mitochondrial supernatant (S-9) fraction of livers from hepatitic LEC rats than in those from Wistar rats. To mimic living cells, we introduced NADPH-generating system (NADPH-gs) into the S-9 incubation system. Thus was ensured a constant supply of NADPH to vital enzymes that may be directly or indirectly involved in the generation and/or elimination of reactive oxygen species (ROSs), such as glutathione reductase (GSSG-R), which require NADPH for their reactions. The levels of LPO in liver S-9 from hepatitic LEC rats were further increased by incubating liver S-9 at 37 degrees C in the presence of NADPH-gs. This increase was inhibited by EDTA, butylated hydroxytoluene (BHT), and catalase (CAT), suggesting that some metal, most likely the accumulated Cu, and ROSs derived from hydrogen peroxide (H2O2) are involved in the increased levels of LPO in the livers of hepatitic LEC rats. The requirement of NADPH-gs for enhanced LPO in the livers of hepatitic LEC rats indicates the consumption of NADPH during reactions leading to LPO. It is known that H2O2, and consequently hydroxyl radical are generated during Cu-catalyzed glutathione (GSH) oxidation. The cyclic regeneration of GSH from GSSG by NADPH-dependent GSSG-R in the presence of NADPH-gs may cause sustained generation of hydroxyl radical in the presence of excess free Cu. The generation of H2O2 in S-9 fraction of livers from hepatitic LEC rats was observed to be significantly higher than that in S-9 fraction of livers from non-hepatitic LEC rats and Wistar rats. Moreover, in addition to the reported decrease in glutathione peroxidase (GPX) activity, we found that CAT activity was markedly decreased in LEC rats with hepatitis. The increased generation of H2O2 with reduced activities of GPX and CAT may result in cellular accumulation of H2O2 in the liver of hepatitic LEC rats. Taken altogether, it is suggested that the accumulated H2O2 undergoes the Fenton-type reaction with also accumulated free Cu, thus generating hydroxyl radical in the livers of hepatitic LEC rats and increasing LPO levels in these animals.
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PMID:Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon (LEC) rats. 1065 Sep 17

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

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