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)

Cytochromes P450 and UDP-Glucuronosyltransferases (UGT) are targets of microsomal autoantibodies in liver and kidney (LKM). LKM autoantibodies are observed in autoimmune hepatitis, in some patients with viral hepatitis, drug-induced hepatitis and autoimmune hepatitis as disease component of the autoimmune polyglandular syndrome type 1 (APS-1). In autoimmune hepatitis LKM antibodies are markers of autoimmune hepatitis type 2. The major target of LKM-1 antibodies is cytochrome P450 2D6; a second less frequent target was the described UGTs of family 1. In autoimmune hepatitis LKM-1 autoantibodies are usually directed against small linear epitopes. LKM autoantibodies are also associated with infection with hepatitis viruses C and D. In hepatitis C about 1-2% of patients develop LKM-1 autoantibodies. About 60% of these autoantibodies are conformation dependent. The presence of LKM autoantibodies in hepatitis C may be associated with an increased risk in interferon treatment. LKM-3 autoantibodies are found in about 8% of patients with hepatitis D and are directed against conformational epitopes. Patients treated with certain drugs may develop drug induced hepatitis. In hepatitis induced by tienilic acid, tienilic acid is activated by and covalently bound to cytochrome P450 2C9. Activation of the immune system results in the formation of autoantibodies against cytochrome P450 2C9 (LKM-2) and infiltration of the liver with immune cells. A similar mechanism has been described for dihydralazine induced hepatitis, where autoantibodies are directed against P450 1A2 (LM). Autoantibodies directed against cytochrome P450 1A2 also are found in patients suffering from hepatitis as a disease component of APS-1.
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PMID:Cytochrome P450 enzymes and UDP-glucuronosyltransferases as hepatocellular autoantigens. 911 34

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
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PMID:Chemical toxicity and reactive oxygen species. 911 92

Enzymes of phase I (cytochromes P450) and phase II (UDP [uridine diphosphate]-glucuronosyltransferases) of drug metabolism are targets of autoimmunity in the following chronic liver diseases of different etiology: 1)autoimmune hepatitis (AIH); 2) hepatitis associated with the autoimmune polyendocrine syndrome type 1 (APS-1); 3) virus-induced autoimmunity; and 4) drug-induced hepatitis. AIH is diagnosed by the following: the absence of infection with hepatitis viruses; the presence of a threshold of relevant factors, including circulating autoantibodies, hypergammaglobulinemia, female sex (female/male ratio 4:1), human leukocyte antigen (HLA) B8, DR3, or DR4; and benefit from immunosuppression. Patients with autoimmune hepatitis type 2 (AIH-2) are characterized by antibodies directed against liver and kidney microsomes, by an early onset of autoimmune hepatitis, which is a more aggressive course of the disease, and by a higher prevalence of autoimmunity directed against other organs. The major target of autoimmunity in patients with AIH-2 is cytochrome P450 2D6. Epitope mapping experiments revealed four short linear epitopes on cytochrome P450 2D6, recognized by liver/kidney microsomal autoantibodies type 1 (LKM-1) in patients with AIH-2. In addition, about 10% of the patient sera contain autoantibodies that detect a conformational epitope on UDP-glucuronosyltransferases (UGTs) of family 1. Presently, LKM-1 autoantibodies are used as diagnostic markers for AIH-2. It is unclear whether these autoantibodies have a pathogenetic role. Hepatitis is found in some patients with APS-1. Presumably this also is an autoimmune liver disease. APS-1 patients with hepatitis may develop autoantibodies directed against microsomal P450 enzymes of the liver; however, these autoantibodies do not recognize cytochrome P450 2D6, but they do recognize cytochrome P450 1A2. Autoimmunity in patients with APS-1 usually is directed against several organs simultaneously, and several organ specific autoantibodies may exist. Interestingly, APS-1 patients may produce various anti-cytochrome P450 antibodies. In addition to the hepatic anti-cytochrome P450, 1A2 autoantibodies are directed against steroidogenic cytochromes P450, namely P450 c21, P450 scc, and P450 c17. These autoantibodies correlate with adrenal and ovarian failure and often these steroidal cell autoantibodies precede the manifestation of adrenal or ovarian dysfunction. Whether anti-P450 1A2 autoantibodies have a similar predictive value is not yet known. LKM autoantibodies are further found in association with chronic hepatitis C and D. In chronic hepatitis C, the major target of LKM autoantibodies is cytochrome P450 2D6. Predominantly, conformational epitopes are recognized by LKM-1 sera of patients with chronic hepatitis C. In 13% of patients with chronic hepatitis D, LKM-3 autoantibody is detectable. The target proteins are UGTs of family 1 and in a minority of sera UGTs of family 2. The epitopes are conformational. All hepatic diseases discussed earlier have in common that autoimmunity, which is directed against enzymes of drug metabolizing multigene families. Each disease is characterized by a specific pattern of autoantibodies, with apparently little overlap. For example, LKM-1 autoantibodies, which are directed against P450 2D6, seem to overlap between AIH and chronic hepatitis C. However, a close examination of these autoantibodies shows differences between LKM-1 autoantibodies from patients with chronic hepatitis C and with AIH. In AIH, LKM autoantibodies are more homogenous, titers are higher, and major autoepitopes on cytochrome P450 2D6 are small and linear. LKM autoantibodies in viral hepatitis C are more heterogeneous and there are multiple epitopes, many of which are conformational. These differences indicate the different mechanisms that are involved in the generation of autoimmunity. (ABSTRACT TRUNCATED)
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PMID:Cytochromes P450 and uridine triphosphate-glucuronosyltransferases: model autoantigens to study drug-induced, virus-induced, and autoimmune liver disease. 932 34

Autoimmunity may be observed in chronic viral hepatitis, in particular hepatitis C and D. The hepatitis C virus (HCV) displays numerous interactions with the immune system. Hepatitis C virus induces a number of diseases of presumed autoimmune background, like mixed cryoglobulinaemia, glomerulonephritis, panarthritis, arthritis, thyroiditis and skin lesions. On the other hand a number of autoantibodies are observed during the course of hepatitis C. Of particular interest are liver/kidney microsomal antibodies (LKM). Their occurrence in viral hepatitis may indicate an increased risk for treatment with interferons. LKM antibodies in chronic hepatitis C recognize several autoepitopes differing from those in autoimmune hepatitis. Hepatitis C-associated LKM antibodies are more heterogeneous. They recognize either conformational or several distinct linear autoepitopes on cytochrome P450 2D6; they may also react with other microsomal proteins. Apart from their molecular weight at 59 and 70 kDa these microsomal antigens are not yet identified. Another model of virus-induced autoimmunity in man is chronic hepatitis D which always requires co-infection with hepatitis B. Hepatitis D is known to be associated with a number of autoantibodies, amongst them LKM-3. LKM-3 antibodies have recently been shown to react with proteins of the UDP glucuronosyltransferase family (UGT). The main antigen is an autoepitope expressed on exon 2-5 of family 1 UGTs. Some hepatitis D sera recognize a minor second epitope on family 2 UGTs. It is interesting that hepatitis C patients recognize proteins of the cytochrome P450 family while hepatitis D sera react with UGTs. There seems to be little overlap between autoimmunity seen in hepatitis C and D as far as autoepitopes are concerned. LKM-3 antibodies against UGT 1 are also seen in a minority of patients with autoimmune hepatitis type 2. However, the autoimmune response against UGTs seen in autoimmune hepatitis differs from that observed in viral hepatitis. Autoantibodies in autoimmune liver disease are usually more homogenous and are directed against precise linear epitopes. Autoepitopes in autoimmune hepatitis usually represent conserved regions of these proteins, the antibody usually is inhibitory and antibody titres are very high. In contrast, autoantibodies in viral hepatitis are more heterogenous, recognize several linear and conformational epitopes; antibody titres are much lower. However, the major LKM autoantigen in chronic hepatitis C also is P450 2D6. Autoimmune hepatitis and autoimmunity in viral hepatitis must be distinguished clinically by all means due to the need for specific therapeutic interventions. These liver diseases may serve as models to study virus induced autoimmunity and autoimmune disease in man.
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PMID:Viral induction of autoimmunity: mechanisms and examples in hepatology. 942 9

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

Halothane hepatitis occurs because susceptible patients mount immune responses to trifluoroacetylated protein antigens, formed following cytochrome P450-mediated bioactivation of halothane to trifluoroacetyl chloride. In the present study, an in vitro approach has been used to investigate the cytochrome P450 isozyme(s) which catalyze neoantigen formation and to explore the protective role of non-protein thiols (cysteine and reduced glutathione). Significant levels of trifluoroacetyl protein antigens were generated when human liver microsomes, and also microsomes from livers of rats pre-treated with isoniazid, phenobarbital or beta-naphtoflavone, were incubated with halothane plus a nicotinamide adenine dinucleotidephosphate (NADPH) generating system. Immunoblotting studies revealed that the major trifluoroacetyl antigens expressed in vitro exhibited molecular masses of 50-55 kDa and included 60 and 80 kDa neoantigens recognized by antibodies from patients with halothane hepatitis. Much lower concentrations of halothane were required to produce maximal antigen generation in isoniazid-induced rat microsomes, as compared with phenobarbital or isosafrole-induced microsomes (0.5 vs 12.5 microl/ml). In isoniazid-induced microsomes, antigen generation was inhibited > 90% by the nucleophiles cysteine and glutathione and by the CYP2E1-selective inhibitors diallylsulfide and p-nitrophenol, but was unaffected by inhibitors of other P450 isozymes (furafylline, sulfaphenazole or triacetyloleandomycin). Neoantigen formation in six human liver microsomal preparations was inhibited in the presence of diallylsulfide, but not by furafylline, sulfaphenazole or triacetyloleandomycin, and exhibited marked variability which correlated with CYP2E1 levels. These results suggest that the balance between metabolic bioactivation by CYP2E1 and detoxication of reactive metabolites by cellular nucleophiles could be an important metabolic risk factor in halothane hepatitis.
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PMID:Interindividual variability in P450-dependent generation of neoantigens in halothane hepatitis. 987 5

To investigate the role of nitric oxide (NO) in hepatitis-induced endotoxemia, we injected mice intraperitoneally with 250 mg/kg galactosamine (GalN) and 1 mg/kg lipopolysaccharide (LPS) separately and in combination. NO synthesis increased in a dose-dependent manner with LPS. NO generation at 5 hr after administration of LPS was greater than that at 24 hr. Enhancement of NO generation was demonstrated in mice administered GalN and LPS in combination. A nitrosyl-heme signal in 10,000 g supernatant of liver homogenate, due to cytochrome P450 (P450) combining with NO, NO-P450, was detected at more than ten hr and even more after administration of LPS by electron spin resonance (ESR) measurements at 77 degrees K. The strongest NO-P450 signal and most extreme elevation of aspartate oxoglutarate aminotransferase (AST), alanine oxoglutarate aminotransferase (ALT), and lactate dehydrogenase (LDH) in serum and of lysosomal enzyme activity in plasma were observed in the GalN + LPS group. Their potency was greater than in the 10 mg/kg LPS group, which was even greater than in the LPS 1 mg/kg group. The aniline hydroxylase activity was inversely proportional to NO-P450 signal intensity. It appears that NO might contribute to LPS-induced hepatic damage in GalN-sensitized mice through degeneration and inactivation of liver microsomal enzymes by binding P450 active sites.
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PMID:NO contribution to lipopolysaccharide-induced hepatic damage in galactosamine-sensitized mice. 1007 39

Tienilic acid (TA) is responsible for an immune-mediated drug-induced hepatitis in humans, while its isomer (TAI) triggers a direct hepatitis in rats. In this study, we describe an immunological approach developed for studying the specificity of the covalent binding of these two compounds. For this purpose, two different coupling strategies were used to obtain TA-carrier protein conjugates. In the first strategy, the drug was linked through its carboxylic acid function to amine residues of carrier proteins (BSA-N-TA and casein-N-TA), while in the second strategy, the thiophene ring of TA was attached to proteins through a short 3-thiopropanoyl linker, the corresponding conjugates (BSA-S-5-TA and betaLG-S-5-TA) thus preferentially presenting the 2, 3-dichlorophenoxyacetic moiety of the drug for antibody recognition. The BSA-S-5-TA conjugate proved to be 30 times more immunogenic than BSA-N-TA. Anti-TA-protein adduct antibodies were obtained after immunization of rabbits with BSA-S-5-TA (1/35000 titer against betaLG-S-5-TA in ELISA). These antibodies strongly recognized the 2, 3-dichlorophenoxyacetic moiety of TA but poorly the part of the drug engaged in the covalent binding with the proteins. This powerful tool was used in immunoblots to compare TA or TAI adduct formation in human liver microsomes as well as on microsomes from yeast expressing human liver cytochrome P450 2C9. TA displayed a highly specific covalent binding focused on P450 2C9 which is the main cytochrome P450 responsible for its hepatic activation in humans. On the contrary, TAI showed a nonspecific alkylation pattern, targeting many proteins upon metabolic activation. Nevertheless, this nonspecific covalent binding could be completely shifted to a thiol trapping agent like GSH. The difference in alkylation patterns for these two compounds is discussed with regard to their distinct toxicities. A relationship between the specific covalent binding of P450 2C9 by TA and the appearance of the highly specific anti-LKM2 autoantibodies (known to specifically recognize P450 2C9) in patients affected with TA-induced hepatitis is strongly suggested.
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PMID:Opposite behaviors of reactive metabolites of tienilic acid and its isomer toward liver proteins: use of specific anti-tienilic acid-protein adduct antibodies and the possible relationship with different hepatotoxic effects of the two compounds. 1007 92

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

Cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) are targets of autoantibodies in several hepatic and extrahepatic autoimmune diseases. Autoantibodies directed against hepatic CYPs and UGTs were first detected by indirect immunofluorescence as antiliver and/or kidney microsomal antibodies. In autoimmune hepatitis (AIH) type 2, liver and/or kidney microsomal (LKM) type 1 autoantibodies are detected and are directed against CYP2D6. About 10% of AIH-2 sera further contain LKM-3 autoantibodies directed against family 1 UGTs. Chronic infections by hepatitis C virus and hepatitis delta virus may induce several autoimmune phenomena, and multiple autoantibodies are detected. Anti-CYP2D6 autoantibodies are detected in up to 4% of patients with chronic hepatitis C, and anti-CYP2A6 autoantibodies are detected in about 2% of these patients. In contrast, 14% of patients with chronic hepatitis delta virus infections generate anti-UGT autoantibodies. In a small minority of patients, certain drugs are known to induce immune-mediated, idiosyncratic drug reactions, also known as 'druginduced hepatitis'. Drug-induced hepatitis is often associated with autoantibodies directed against hepatic CYPs or other hepatic proteins. Typical examples are tienilic acid-induced hepatitis with anti-CYP2C9, dihydralazine hepatitis with anti-CYP1A2, halothane hepatitis with anti-CYP2E1 and anticonvulsant hepatitis with anti-CYP3A. Recent data suggest that alcoholic liver disease may be induced by mechanisms similar to those that are active in drug-induced hepatitis. Autoantibodies directed against several CYPs are further detected in sera from patients with the autoimmune polyglandular syndrome type 1. Patients with autoimmune polyglandular syndrome type 1 with hepatitis often develop anti-CYP1A2; patients with adrenal failure develop anti-CYP21, anti- CYP11A1 or CYP17; and patients with gonadal failure develop anti-CYP11A1 or CYP17. In idiopathic Addison disease, CYP21 is the major autoantigen.
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PMID:Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases. 1085 Dec 84


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