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)

The quantitative determination of hydrocarbons exhaled by animals as an in vivo index of extensive lipid peroxidation is described. Advantages and limitations of this method are discussed. Acetaminophen-induced hepatic lipid peroxidation in mice is an example of oxidative stress, the extent of which is determined in vivo by the turnover of endoplasmic reticulum monooxygenase and the cofactor, e.g. glutathione status of the liver. In microsomal suspensions, none of the assay methods for lipid peroxidation identifies acetaminophen as a prooxidant. Rather, it acts like an antioxidant. The obvious limitations of in vitro experiments are emphasized. Cytosolic metabolism of allyl alcohol also leads, in a dose-dependent manner, to extensive lipid peroxidation. Evidence is presented that release of iron from intracellular stores following overproduction of NADH may be the primary cause of this lesion. The term reductive stress is suggested for this metabolic initiation of iron redox cycling. In experimental hepatitis induced by galactosamine/endotoxin, a leukotriene-mediated pathomechanism, no signs of lipid peroxidation are detectable. This means that ethane or pentane formation are definitively not late consequences of membrane deterioration but rather early causal events in special cases of hepatotoxicity.
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PMID:Measurement of in vivo lipid peroxidation and toxicological significance. 331 1

Previous studies have demonstrated that antibodies in sera from patients with halothane hepatitis recognize halothane-induced liver microsomal polypeptide neoantigens, and have suggested that these antibodies may play a role in the pathogenesis of the hepatitis. In the present study, the mechanism of neoantigen generation was investigated. Liver microsomes from rats treated in vivo with halothane or deuterated halothane were tested by immunoblotting for reactivity with patients' sera and with an antiserum specific for the covalently bound trifluoroacetyl (TFA) halide metabolite of halothane. Rat liver microsomes incubated aerobically or anaerobically with halothane or deuterated halothane in vitro, +/- NADPH and/or NADH, were also analyzed. The results obtained demonstrate that neoantigen expression involves oxidative halothane metabolism by cytochromes P-450 to TFA halide and covalent binding of the TFA group to the proteins. Incubation of microsomes from halothane-treated rats with 1 M piperidine cleaved the TFA groups from the proteins and abolished antigenicity, confirming this conclusion. Recognition of the neoantigens by the patients' antibodies was inhibited only partially using the hapten derivative N-E-TFA-L-lysine. It appears that the patients' antibodies recognize epitopes consisting of the TFA group plus associated structural features of the protein carriers (100 kDa, 76 kDa, 59 kDa, 57 kDa and 54 kDa), not the TFA hapten alone. To our knowledge, this constitutes the first characterization of drug metabolite-tissue protein neoantigens implicated in a drug hypersensitivity. The approach described may be of general utility for characterization of drug-induced neoantigens associated with other drug hypersensitivities.
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PMID:Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane. 338 39

Adult female B6C3F1 mice were gavaged with 4,4'-thiobis-(6-t-butyl-m-cresol) (TBBC) in corn oil at doses of 10, 100, or 200 mg/kg daily for 14 consecutive days. There was no overt toxicity, as manifested by grossly observable behavioral changes, decreased growth rate over the exposure period, or mortality. There were also no marked effects on serum chemistries or hematology, with the exception of a significant increase (41%) in the number of leukocytes at the highest dose. Absolute differential counts indicated that significant increases occurred in the number of lymphocytes (31%) and neutrophils (177%). Studies with bone marrow indicated a significant 30% increase in the number of cells/femur from animals treated with the highest dose of TBBC. The number of macrophage progenitors (CFU-M)/femur was significantly increased by 28%, while the number of granulocyte-monocyte progenitors (CFU-GM)/femur was nonsignificantly increased by 20% in the high dose animals. The weight of both the spleen and liver was increased in a dose-related fashion, although the histopathology of the spleen of TBBC-treated mice was not different from control. The livers of mice receiving the high dose showed mild focal hydropic degeneration, mild hepatitis, and a slight increase in the number of Kupffer cells. No other organs were affected. Liver microsomal protein and cytochrome P-450 levels were increased in a dose-related fashion. Enzyme activities of aminopyrine demethylase and aniline hydroxylase, but not arylhydrocarbon hydroxylase, were also increased in a dose-related fashion.
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PMID:An immunotoxicological evaluation of 4,4'-thiobis-(6-t-butyl-m-cresol) in female B6C3F1 mice. 1. Body and organ weights, hematology, serum chemistries, bone marrow cellularity, and hepatic microsomal parameters. 339 95

The metabolism of the anticonvulsant mephenytoin is subject to a genetic polymorphism. In 2-5% of Caucasians and 18-23% of Japanese subjects a specific cytochrome P-450 isozyme, P-450 meph, is functionally deficient or missing. We have accumulated evidence that autoimmune antibodies observed in sera of patients with tienilic acid induced hepatitis (anti-liver kidney microsome 2 or anti-LKM2 antibodies) specifically recognize the cytochrome P-450 involved in the mephenytoin hydroxylation polymorphism. This is demonstrated by immunoinhibition and immunoprecipitation of microsomal (S)-mephenytoin 4-hydroxylation activity and by the recognition by anti-LKM2 antibodies of a single protein band on immunoblots of human liver microsomes after sodium dodecyl sulfate-polyacrylamide gel electrophoresis or isoelectric focusing. The cytochrome P-450 recognized by anti-LKM2 antibodies was immunopurified from microsomes derived from livers of extensive (EM) or poor metabolizers (PM) of (S)-mephenytoin. Comparison of the EM-type cytochrome P-450 to that isolated from PM livers revealed no difference in regard to immuno-cross-reactivity, molecular weight, isoelectric point, relative content in microsomes, two-dimensional tryptic peptide maps, one-dimensional peptide maps with three proteases, amino acid composition, and amino-terminal protein sequence. Finally, the same protein was precipitated from microsomes prepared from the liver biopsy of a subject phenotyped in vivo as a poor metabolizer of mephenytoin. These data strongly suggest that the mephenytoin hydroxylation deficiency is caused by a minor structural change leading to a functionally altered cytochrome P-450 isozyme.
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PMID:Genetic polymorphism of human cytochrome P-450 (S)-mephenytoin 4-hydroxylase. Studies with human autoantibodies suggest a functionally altered cytochrome P-450 isozyme as cause of the genetic deficiency. 344 70

"Anti-liver/kidney microsome" (anti-LKM) autoantibodies have been found in the serum of patients with cryptogenic chronic hepatitis and with immunoallergic drug-induced hepatitis, such as those induced by halothane or by tienilic acid (called anti-LKM2 in this case). So far the nature of the human microsomal macromolecules recognized by these antibodies has not been determined. Here we show, by using immunoblot techniques, that among the macromolecules present in human adult liver microsomes, one protein called cytochrome P-450-8 is specifically recognized by most sera of patients containing anti-LKM2 antibodies but not by control serum. Human fetal liver microsomes that do not contain cytochrome P-450-8 are not recognized by the anti-LKM2 antibodies. It is also shown that anti-cytochrome P-450-8 antibodies as well as human serum containing anti-LKM2 antibodies specifically inhibit the hydroxylation of tienilic acid by human liver microsomes. These results indicate that anti-LKM2 antibodies appearing in patients with hepatitis and concomitant administration of tienilic acid are directed against a cytochrome P-450 isoenzyme that catalyzes the metabolic oxidation of this drug. This suggests a possible mechanism for the appearance of anti-organelle antibodies in a drug-induced hepatitis.
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PMID:Human anti-endoplasmic reticulum autoantibodies appearing in a drug-induced hepatitis are directed against a human liver cytochrome P-450 that hydroxylates the drug. 354 Sep 68

Thirty-six wild-caught woodchucks (Marmota monax) were characterized according to sex, weight, trapping locality, liver pathology, and serum or hepatic markers of woodchuck hepatitis virus. Liver subcellular fractions were assayed for microsomal cytochromes P-450, aryl hydrocarbon hydroxylase, glutathione, cytosolic enzymes involved in its metabolism (glutathione S-transferase, glutathione peroxidase, and glutathione reductase), in the hexose monophosphate shunt (glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase), NADH- and NADPH-dependent diaphorases, and DT diaphorase. Moreover, liver postmitochondrial fractions were assayed for their ability to activate procarcinogens [i.e., a tryptophan pyrolysate product, aflatoxin B1, 2-aminofluorene, and trans-7,8-dihydrobenzo(a)pyrene] to mutagenic metabolites in the Ames reversion test and to decrease the activity of direct-acting mutagens [i.e., 4-nitroquinoline N-oxide, 2-methoxy-6-chloro-9-[3-(2-chloroethyl)aminopropylamino]acridine X 2HCl, and sodium dichromate]. A considerable interindividual variability in metabolism was observed among the examined woodchucks. Some of the investigated parameters were more elevated in virus carriers, especially in those suffering from chronic active hepatitis, but only a few of the recorded differences (i.e., oxidized glutathione reductase and NADPH-dependent diaphorase) were statistically significant. The comparison of the monitored activities in woodchucks and in other rodent species (rat and mouse) led to the conclusion that the liver metabolism of mutagens and carcinogens in woodchucks is more oriented in the sense of activation, while detoxification mechanisms are more efficient in rats and mice.
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PMID:Metabolism of mutagens and carcinogens in woodchuck liver and its relationship with hepatitis virus infection. 360 50

The concentrations of triiodothyronine (T3), thyroxine (T4), T3/T4 ratio, free thyroxine index, and thyroxine-binding globulin were investigated in 114 viral hepatic disease patients and 36 controls. The T3/T4 ratio in healthy hepatitis B virus carriers was significantly greater than those in the controls and fulminant, acute, or chronic active hepatitis patients. The T3/T4 ratio in the fulminant hepatitis patients was significantly less than those in the controls and other liver disease patients. The correlation coefficient between the T3/T4 ratio and microsomal arylamidase activity in liver tissue from 30 patients was 0.78 (p less than 0.001). The correlation coefficient between the T3/T4 ratio and the content of cholinesterase was 0.64 (p less than 0.001). These results suggest that the T3/T4 ratio represents a marker of microsomal function and is useful for estimation of prognosis of fulminant hepatitis or differentiation of various viral hepatic diseases.
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PMID:Serum thyroid hormone, triiodothyronine, thyroxine, and triiodothyronine/thyroxine ratio in patients with fulminant, acute, and chronic hepatitis. 370 63

Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis.
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PMID:Drug interactions and hepatitis produced by some macrolide antibiotics. 387 43

The relationship between hepatic glycerolipids and microsomal drug-metabolizing enzymes was studied in liver biopsies from 41 subjects. The series included obese, diabetic, epileptic and chronic alcoholic patients, all of whom were hospitalized for suspected hepatic ailments (fatty liver, hepatitis or cirrhosis). Therapy with enzyme-inducing anticonvulsants was associated with high phospholipid and cytochrome P-450 and low triacylglycerol concentration in the liver. In patients with fatty liver or cirrhosis low phospholipid and cytochrome P-450 and high triacylglycerol concentrations were observed. There was a significant correlation (r (Pearson's product moment correlation coefficient) = 0.91) between the hepatic phospholipid and cytochrome P-450 concentration. The cytochrome P-450 concentration was inversely related (r = -0.74) to the triacylglycerol concentration. The positive correlation between hepatic phospholipids and drug-metabolizing enzymes could be interpreted as indicating that in human liver phospholipid and cytochrome P-450 synthesis share common regulators, or that phospholipids are necessary for the maximum rate of cytochrome P-450 synthesis.
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PMID:Relationship between lipid composition and drug metabolizing capacity of human liver. 398 78

A study of the clinical associations of a recently defined tissue autoantibody, the liver/kidney microsomal (L.K.M.) antibody, showed that out of 33 patients 26 had clinical liver disease. Fifteen of the patients had active chronic hepatitis and there were seven cases of acute hepatitis, precipitated by presumed virus A infection in three instances and by drug hypersensitivity in the other four. The remaining cases with liver disease included two with subclinical hepatitis and two with hepatocellular carcinoma. Evidence is presented that the patients with active chronic hepatitis may represent a distinct subgroup of the disease with a young mean age, an even male to female ratio, and a striking lack of other nonorgan-specific autoantibodies-that is, antinuclear and smooth muscle-which are usually present in the other autoimmune variant of the disease.
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PMID:Hepatic disorders associated with liver-kidney microsomal antibodies. 459 2


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