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

Aromatic anticonvulsants such as phenytoin, phenobarbital and carbamazepine are associated with a hypersensitivity syndrome (fever, rash lymphadenopathy, hepatitis) suggestive of an immune component. We have identified immunoglobulin G antibodies in the sera of nine affected patients which recognize a 53-kD protein which is constitutively expressed and PB inducible in rat liver microsomes. No such reactivity was observed in sera from healthy controls, patients on chronic phenytoin therapy without toxicity or patients with hepatic failure not receiving anticonvulsants. Using highly purified rat hepatic cytochrome P450, P450 3A1 was identified as the major antigenic species, whereas less intense reactivity was noted with P450 2C11. P450 2C6 and 3A2 were minor antigens in some patients. In all patients, the apparent constitutive and phenobarbital-inducible expression of the antigen was a composite effect of antibodies reacting with at least two isozymes, one of which was constitutively expressed and the other PB inducible. In human liver, a 53-kD antigen was expressed to a greater extent in microsomes from a patient with a fatal hepatotoxic reaction to phenytoin compared to microsomes from normal liver or from a sulfonamide hepatitis patient. Western blotting with microsomes prepared from lymphoblastoid cell lines transfected with different human hepatic cytochromes P450 failed to identify P450s 1A1, 1A2, 2A3, 2B6, 2C9, 2D6, 2E1, 3A4 or epoxide hydrolase as the target antigen. Identification of the antigen will be important in understanding the relationship between drug metabolism and the subsequent immune response in the pathogenesis of these rare but severe forms of drug toxicity.
 ...
PMID:Human anti-cytochrome P450 antibodies in aromatic anticonvulsant-induced hypersensitivity reactions. 140 97

Antimicrosomal antibodies in inflammatory liver diseases all seem to be directed against members of the cytochrome P450 family of proteins. These autoantigens seem to be genetically polymorphic, the autoantibodies are inhibitory, and the autoepitopes are generally conserved among species. Anti-P450 autoantibodies share these characteristics with other autoantibodies, for example, antinuclear antibodies in systemic lupus erythematosus. The identification of P450s as human autoantigens is clinically important. Diagnostic tests will be developed on the basis of cloned antigen, facilitating a better diagnosis of drug-induced and idiopathic autoimmune hepatitis. It is unknown what triggers autoantibody production against cytochrome P450 proteins. Furthermore, their pathogenetic role and thus their involvement in tissue destruction is unclear. In this context LKM1 autoantibodies may serve as a model. Although LKM1 antibodies are inhibitory, all LKM1 antibody-positive patients tested so far are extensive metabolizers for drug metabolism mediated by P450IID6 and express this protein in their livers. Thus, the inhibitory LKM1 autoantibody does not sufficiently penetrate through the intact liver cell membrane to inhibit enzyme function in vivo. Presumably, tissue destruction in autoimmune hepatitis is mediated by liver-infiltrating T lymphocytes. T lymphocytes have been cloned from liver tissue that specifically proliferate in the presence of recombinant cytochrome P450IID6. The construction of overlapping cDNA subclones is also valuable to identify immunodominant B cell as well as relevant T cell epitopes.
 ...
PMID:Identification of human cytochrome P450s as autoantigens. 178 10

The authors report a case of toxic hepatitis in a woman of 22 years of age in the third trimester of her first pregnancy treated by methyldopa for hypertension of pregnancy which was diagnosed at 33 weeks of amenorrhoea. The prodromal symptoms were mild and consisted of nausea, vomiting and rise in temperature and this phase was associated with febrile jaundice without pruritus and it was only associated with coagulation disorders in the third stage of labour. This was a case of mixed cytolytic hepatitis (ASAT x 3N) and cholestasis (x 1.5N). The outcome was fatal. The patient died three days after delivery following haematemesis and renal failure as well as hepatic encephalopathy. The main diagnostic feature was acute hepatic stasis in spite of the absence of pruritus and the presence of a raised temperature after hematolytic, viral and obstructive causes had been eliminated. Histology confirmed that there was toxic hepatitis. This aetiology was suggested by the timing of the symptoms after MD (methyldopa) had been taken. Elkington described methyldopa hepato-toxicity in 1969. Fatal cases in the literature were in patients who were over 40 years of age. Methyldopa is used in pregnant women because of its safety as far as the fetus is concerned. Mechanism by which it causes toxic hepatitis is a combination of abnormal metabolism (the cytochrome P450 chain produces an antigen) and an immune reaction in response to this antigen and these explain why such severe and potentially fatal forms of the condition exist.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:[Fatal toxic hepatitis in pregnancy. A discussion of the role of methyldopa]. 232 42

Toxicological studies using primary cultured hepatocytes were reviewed. Primary cultures of mature hepatocytes retain many liver functions and various hormonal responses for long term. Therefore, this system overcomes various limitations of another in vitro system using liver. Toxicological studies using primary cultured hepatocytes showed high correlation to in vivo studies, for example, in vitro screening of inducible chemicals of hepatitis, and unscheduled DNA synthesis activity, etc. But there still remain some shortcomings, for example, rapid loss of cytochrome P450 and other drug metabolizing enzymes. A number of attempts to modify culture conditions resulted in long term maintenance of these enzymes. Recently Guzelian and colleagues established that using matrigel coated dishes, primary cultured hepatocytes expressed highly and maintained cytochrome P450 and other specific genes for long periods like in vivo. In the future study using cultured hepatocytes, if it can culture more long term or subculture as maintenance liver functions, not only rodent hepatocytes but also human hepatocytes are more useful for toxicological assessments and screening of drugs for liver diseases.
 ...
PMID:[Use of primary cultured hepatocytes for toxicology]. 263 99

Children with autoimmune hepatitis have high serum titers of antibodies directed against a 50-kD protein of rat liver endoplasmic reticulum. Affinity-purified anti-50-kD antibodies were used to screen a rat liver cDNA library in lambda GT-11 expression vector. 12 immunopositive clones were obtained. Crossreactivities between fusion proteins of these clones and the 50-kD protein was demonstrated, and four clones were analyzed by restriction mapping, one of them by nucleotide sequencing. Complete identity was found between the restriction maps of two clones (LKMC1 and LKMC2) and that of the 5' end of the rat cytochrome P450 db2. Sequence of a 608-bp fragment of LKMC1 showed complete homology with the rat P450 db2 form. The restriction map of the other two clones (LKMC3 and LKMC4) was identical to that of rat P450 db1. These results suggest that the antigen recognized by LKMA is a P450 of the IID subfamily.
 ...
PMID:Anti-liver kidney microsome antibody recognizes a cytochrome P450 from the IID subfamily. 284 31

The authors have studied the action of fluorine, administered by inhalation, on the liver metabolism of a chemical carcinogen: dimethylnitrosamine (DMN). The results demonstrate a decrease in the level of cytochrome P450 and in the activity of benzo(a)pyrene hydroxylase in animals treated with DMN or DMN + HF. The greater inhibition in the presence of HF is paralleled by a decrease in the weight of the liver and in the synthesis of liver microsomal proteins. This reduction of activity (with the exception of dimethylnitrosamine demethylase which is unaffected) is supported by the result of the histological examinations showing two different types of lesion-necrotic toxic hepatitis and post-hepatitic cirrhosis - the frequency of which is much higher in the presence of fluorine.
 ...
PMID:[Effect of HF on the hepatic metabolism of dimethylnitrosamine in the rat]. 667 13

Synergy between exposure to chemical carcinogens (nitrosamines) and infestation with the liver fluke Opisthorchis viverrini has been demonstrated in a hamster model of hepatocarcinogenesis (Flavell et al., Carcinogenesis 4:927-930, 1983; Thamavit et al., Carcinogenesis 8:1351-1353, 1987). To elucidate the mechanisms of this interaction we tested the hypothesis that liver parasitism might influence the expression and activity of carcinogen metabolizing enzymes. We found that one, and perhaps more, hamster liver cytochrome P450 (CYP) isozymes immunorelated to mouse CYP2A5 contributed up to 50 or 60% of the hepatic aflatoxin B1 (AFB) and N-nitrosodiethylamine (NDEA) metabolism, respectively. As inferred from average enzyme activities and from western blot, immunoinhibition, and substrate (coumarin) inhibition analyses, O. viverrini infestation increased the expression of enzymes detectable by anti-CYP2A5 antibody as well as NDEA metabolism in male but not in female hamsters. Immunohistochemical analysis of CYP2A expression by anti-mouse CYP2A5 antibody demonstrated that the O. viverrini-associated increase was not uniformly distributed throughout the liver but occurred in hepatocytes immediately adjacent to areas of inflammation. Immunohistochemical analysis of AFB-DNA adducts in the livers of O. viverrini-infested hamsters treated with AFB showed that the highest levels of adducts were found in the regions of liver where hepatocellular expression of enzymes detectable by anti-CYP2A5 antibody is induced. These results suggest that a high local expression of CYP isozymes in O. viverrini-infested livers could be a contributing risk factor in the development of liver cancers associated with parasitic hepatitis.
 ...
PMID:Association of liver fluke (Opisthorchis viverrini) infestation with increased expression of cytochrome P450 and carcinogen metabolism in male hamster liver. 791 96

In previous studies, immune responses to novel, halothane-induced hepatic antigens have been implicated in the mechanism of halothane hepatitis. Experiments performed using the technique of immunoblotting have indicated that the halothane-induced antigens comprise a group of halothane metabolite-modified microsomal proteins (trifluoroacetylated proteins). In the present report, we describe detection of an additional and quite distinct group of halothane-induced antigens. The novel halothane-induced antigens were expressed in microsomal fractions from livers of halothane-treated rats and could be detected by enzyme-linked immunosorbent assay (ELISA), but not by immunoblotting. In contrast to the major trifluoroacetyl-protein antigens detectable by immunoblotting, which were soluble in buffer containing 0.1% sodium deoxycholate, the novel antigens detectable by ELISA were not soluble in 0.1% sodium deoxycholate but were soluble in 2% sodium deoxycholate. Expression of the novel antigens was reduced markedly when rats were treated with deuterated halothane, in place of halothane. This suggests that their expression requires metabolism of halothane via the same oxidative, cytochrome P450-mediated pathway known to be responsible for generation of the antigens detectable by immunoblotting. Both the antigens detectable by ELISA and the antigens detected by immunoblotting were expressed slowly in livers of halothane-treated rats and were long-lived. Overall, these results indicate that the technique of immunoblotting is of limited value for detection and characterization of antigens involved in immune-mediated adverse drug reactions.
 ...
PMID:Sera from patients with halothane hepatitis contain antibodies to halothane-induced liver antigens which are not detectable by immunoblotting. 793 86

The hepatotoxicity of flutamide, an antiandrogen that produces hepatitis in some human recipients, was studied in isolated rat hepatocytes. Flutamide (1 mM) led to the covalent binding of reactive electrophilic metabolites to male rat hepatocyte proteins. It decreased the reduced glutathione (GSH)/glutathione disulfide ratio and total protein thiols. This was associated with an early increase in phosphorylase a activity (a Ca(++)-dependent enzyme) and a decrease in cytoskeleton-associated protein thiols, the formation of plasma membrane blebs, the release of lactate dehydrogenase (LDH) and a loss of cell viability. Both covalent binding and LDH release were decreased by piperonyl butoxide (an inhibitor of cytochrome P450) and increased by dexamethasone pretreatment (which induces cytochrome P450 3A). The toxicity was increased by beta-naphthoflavone (which induces cytochrome P450 1A). Hepatocytes from female rats (which lack cytochrome P450 3A2) exhibited lower covalent binding and lower LDH release. The addition of cystine (a GSH precursor) increased hepatocellular GSH and decreased LDH release in male hepatocytes. The administration of a diet deficient in sulfur-containing amino acids had the opposite effects; it produced toxicity with 100 microM flutamide. Flutamide (50 microM) markedly inhibited respiration (mainly at the level of complex I) in isolated male rat liver mitochondria and flutamide (1 mM) decreased ATP levels in isolated male rat hepatocytes. It was concluded that flutamide is toxic to rat hepatocytes as a result of the cytochrome P450 (3A and also 1A)-mediated formation of electrophilic metabolites, whose damaging effects are further aggravated by the inhibitory effect of flutamide on mitochondrial respiration and ATP formation.
 ...
PMID:Toxicity of the antiandrogen flutamide in isolated rat hepatocytes. 801 83

The antihypertensive drug dihydralazine may, on rare occasions, cause immunoallergic hepatitis characterized by anti-cytochrome P450 (P450)1A2 autoantibodies. To understand the first steps leading to this immune reaction, we studied the covalent binding fo dihydralazine metabolites to microsomes from rat and human livers. Upon incubation with NADPH and microsomes, dihydralazine formed metabolites that reacted with heme (as evidenced by destruction of heme, formation of 445-nm light-absorbing complexes, and covalent binding of heme to P450 apoprotein) and covalently bound to microsomal proteins. Formation of these metabolites was shown (by NADPH dependence, induction by beta-naphthoflavone, and immunoinhibition by anti-P4501A antibodies) to be mediated by P4501A. Finally, these metabolites appeared to bind to P4501A2, which produced them. These results support the following scheme for the first steps of this autoimmune reaction: P4501A2 metabolizes dihydralazine into reactive metabolites that then bind to it, forming a neoantigen that triggers an immune response characterized by autoantibodies against P4501A2.
 ...
PMID:Interactions of dihydralazine with cytochromes P4501A: a possible explanation for the appearance of anti-cytochrome P4501A2 autoantibodies. 802 22


1 2 3 4 5 6 7 8 9 Next >>