Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Identification of human cytochrome P450s as autoantigens. 178 10

The three best-described genetic polymorphisms of drug metabolism--the debrisoquin/sparteine type of oxidative polymorphism (hereafter referred to as the debrisoquin polymorphism), the polymorphism of N-acetylation, and the mephenytoin type of oxidative polymorphism--are reviewed. For all three polymorphisms, the poor-metabolizer phenotype is inherited as an autosomal recessive trait. The debrisoquin and mephenytoin oxidative polymorphisms involve defects in two separate cytochrome P450 enzymes. The prevalence of the poor-metabolizer phenotype for debrisoquin ranges between 2% and 10% for groups of various ethnic origins. The poor-metabolizer phenotype for mephenytoin comprises about 5% of the Caucasian population and about 20% of the Japanese population. N-acetyltransferase is a cytosolic enzyme whose clinical polymorphism was discovered using isoniazid as the substrate probe. The prevalence of the slow-acetylator phenotype among American and European Caucasian and American black groups is about 50%; among the Japanese it is about 10%. More than 20 agents are substrates for debrisoquin hydroxylase, about 15 for N-acetyltransferase, and 3-5 for mephenytoin. In poor metabolizers, debrisoquin can cause hypotension, and sparteine can cause blurred vision, headache, and dizziness. Clinical consequences of the slow-acetylator phenotype include increased susceptibility to systemic lupus erythematosus induced by procainamide and hydralazine, peripheral neuropathy induced by isoniazid, hydralazine, and dapsone, and sulfasalazine-induced dose-related leukopenia, nausea, vomiting, headache, and vertigo. After administration of mephenytoin, poor metabolizers have increased somnolence and intellectual impairment. Awareness of genetic polymorphisms of drug metabolism should improve understanding of interindividual variability in drug disposition and response.
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PMID:Polymorphic drug metabolism. 268 60

Cytochromes P450 comprise a superfamily of enzymes pivotal in the metabolism of innumerable substrates of both endogenous and exogenous origin. The total number of distinct P450 genes, each encoding a different enzyme in humans, is estimated to be at least 60 and possibly several hundred. The cytochrome P450 (CYP) superfamily nomenclature system is based on divergent evolution of the genes. Most of the enzymes within gene families CYP1, CYP2, CYP3 and CYP4 appear to have evolved as the body's primary defense against the onslaught of chemicals confronted on a daily basis. Whereas P450 enzymes more than 3.5 billion years ago were undoubtedly designed as necessary components of signal transduction pathways, in the past billion years most P450 enzymes have become generally responsible for the detoxification of numerous foreign chemicals. During such oxidative metabolism, it has become increasingly apparent that these enzymes are also capable of functioning in an ambivalent manner, generating toxic intermediates. More than a dozen human P450 polymorphisms have been characterized. Genetic variability in P450 expression is therefore likely to have significant bearing on individual susceptibility to chemical toxicity. In this review, genetic differences in human P450 expression are outlined, and their possible relationship to autoimmune disease is examined. In addition, the speculative role of P450 polymorphisms in several 'lupus-like' disorders is discussed.
Lupus 1994 Dec
PMID:Possible role of cytochromes P450 in lupus erythematosus and related disorders. 770 4

Previous reports of an association between the polymorphic cytochrome P450 CYP2D6 and systemic lupus erythematosus are conflicting. Following the elucidation of the molecular basis of the CYP2D6 genetic polymorphism, we re-examined the hypothesis of an association of this gene with a susceptibility to system lupus erythematosus by analysing the complete CYP2D6 coding sequence. For this purpose, we studies the occurrence of 16 mutations in genomic DNA from 69 systemic lupus erythematosus patients and a large control group using a previously described polymerase chain reaction-single strand confirmation polymorphism analysis. In addition, we studied the occurrence of 11 alleles and 21 genotypes in the same individuals by the combined use of restriction fragment length polymorphism and allele-specific polymerase chain reaction followed by polymerase chain reaction-single strand confirmation polymorphism analysis. No significant differences in the distribution of overall genotypes and predicted phenotypes were observed between system lupus erythematosus patients and controls. The only new finding of our study is the higher frequency of one non functional allele, namely the CYP2D6*4A, in systemic lupus erythematosus versus control individuals (P = 0.007). This increased frequency was not statistically significant in multiple comparison analysis and was not related to any specific clinical features of systemic lupus erythematosus. These results suggest that CYP2D6 genotype as well as CYP2D6 phenotype are not determinant of susceptibility to systemic lupus erythematosus but the presence of the inactive CYP2D6*4A allele may be a contributory factor.
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PMID:Genetic analysis of the cytochrome P450 CYP2D6 polymorphism in patients with systemic lupus erythematosus. 968 64

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.
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PMID:Involvement of CYP2D6 activity in the N-oxidation of procainamide in man. 1063 31

Up to 5% of all hospital admissions are the result of adverse drug reactions (ADRs). Identifying those factors which may predispose to ADRs is essential for risk management. Amongst the known risk factors for adverse reactions are increasing age, polypharmacy, liver and renal disease as well as being female. Female patients have a 1.5- to 1.7-fold greater risk of developing an ADR, including adverse skin reactions, compared with male patients. The reasons for this increased risk are not entirely clear but include gender-related differences in pharmacokinetic, immunological and hormonal factors as well as differences in the use of medications by women compared with men. Women generally have a lower lean body mass, a reduced hepatic clearance, have differences in activity of cytochrome P450 (CYP) enzymes (40% increase in CYP3A4, varied decrease in CYP2D6, CYP2C19 and CYP1A2), and metabolize drugs at different rates compared with men. Other important factors include conjugation, absorption, protein binding and renal elimination, which may all have some gender-based differences. However, how these differences result in an increased risk of ADRs is not clear. There are pharmacodynamic differences between men and women, seen particularly with cardiac and psychotropic medications. There is no doubt that chlorpromazine, fluspirilene and various antipsychotics appear more effective in women than men for the same dosage and plasma concentration. Similarly, women are at increased risk of QT prolongation with certain anti-arrhythmic drugs compared with men even at equivalent serum concentrations. The mechanisms are unknown. Increasingly the evidence is that idiosyncratic drug reactions, particularly cutaneous reactions, appear to have an immunological etiology. It is possible that gender difference in T cell activation and proliferation account for this as well as the increased prevalence of skin diseases such as systemic lupus erythematosus and photosensitivity. Whatever the mechanism(s), it is important to be aware that gender is a significant factor in ADRs.
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PMID:Do women have more adverse drug reactions? 1177 Mar 89

A great many cardiovascular drugs (CVDs) have the potential to induce adverse reactions in the mouth. The prevalence of such reactions is not known, however, since many are asymptomatic and therefore are believed to go unreported. As more drugs are marketed and the population includes an increasing number of elderly, the number of drug prescriptions is also expected to increase. Accordingly, it can be predicted that the occurrence of adverse drug reactions (ADRs), including the oral ones (ODRs), will continue to increase. ODRs affect the oral mucous membrane, saliva production, and taste. The pathogenesis of these reactions, especially the mucosal ones, is largely unknown and appears to involve complex interactions among the drug in question, other medications, the patient's underlying disease, genetics, and life-style factors. Along this line, there is a growing interest in the association between pharmacogenetic polymorphism and ADRs. Research focusing on polymorphism of the cytochrome P450 system (CYPs) has become increasingly important and has highlighted the intra- and inter-individual responses to drug exposure. This system has recently been suggested to be an underlying candidate regarding the pathogenesis of ADRs in the oral mucous membrane. This review focuses on those CVDs reported to induce ODRs. In addition, it will provide data on specific drugs or drug classes, and outline and discuss recent research on possible mechanisms linking ADRs to drug metabolism patterns. Abbreviations used will be as follows: ACEI, ACE inhibitor; ADR, adverse drug reaction; ANA, antinuclear antigen; ARB, angiotensin II receptor blocker; BAB, beta-adrenergic blocker; CCB, calcium-channel blocker; CDR, cutaneous drug reaction; CVD, cardiovascular drug; CYP, cytochrome P450 enzyme; EM, erythema multiforme; FDE, fixed drug eruption; I, inhibitor of CYP isoform activity; HMG-CoA, hydroxymethyl-glutaryl coenzyme A; NAT, N-acetyltransferase; ODR, oral drug reaction; RDM, reactive drug metabolite; S, substrate for CYP isoform; SJS, Stevens-Johnson syndrome; SLE, systemic lupus erythematosus; and TEN, toxic epidermal necrolysis.
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PMID:ORAL ADVERSE DRUG REACTIONS TO CARDIOVASCULAR DRUGS. 1476 98

In transplant recipients, immunosuppressive treatment affects cell-mediated immunity and increases the risk of tuberculosis. Tuberculosis may be transmitted by the donor organ or occur de novo, but such cases are rare. The vast majority of cases of active tuberculosis in transplant recipients result from reactivation of latent Mycobacterium tuberculosis infection. The incidence varies from one region of the globe to another, from 0.5-1.0% in North America, to 0.36-5.5% in Europe and 7.0-11.8% in India. The incidence of tuberculosis among transplant recipients is much higher than in the general population. Diabetes mellitus, renal impairment, systemic lupus erythematosus, chronic liver disease and AIDS all increase the risk of post-transplant tuberculosis. Extrapulmonary and disseminated forms are frequent in this setting. The diagnosis of tuberculosis in transplant recipients is often difficult, and treatment is frequently delayed. Tuberculosis can be life-threatening in such cases. Treatment is difficult because rifampicin is a cytochrome P450 inducer (leading to reduced levels of cyclosporine), and because the hepatotoxicity of isoniazid, rifampin and pyrazinamide is frequently increased in transplant recipients. Treatment of latent tuberculosis before transplantation markedly reduces the risk of developing active tuberculosis after transplantation.
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PMID:[Mycobacterium tuberculosis infection following organ transplantation]. 1765 Jul 54

Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.
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PMID:The chemical defensive system in the pathobiology of idiopathic environment-associated diseases. 2020 26

The recommended systemic therapy of choice for discoid lupus erythematosus (DLE) is the 4-aminoquinolone antimalarial hydroxychloroquine. There is limited published information on the likelihood of clinical response and, in particular, what factors influence outcome. We conducted a multicenter observational and pharmacogenetic study of 200 patients with DLE treated with hydroxychloroquine. The primary outcome was clinical response to hydroxychloroquine. We investigated the effects of disease attributes and metabolizing cytochrome P450 (CYP) polymorphisms on clinical outcome. Although the majority of patients responded to hydroxychloroquine, a significant proportion (39%) either failed to respond or was intolerant of the drug. Cigarette smoking and CYP genotype did not have any significant influence on response to hydroxychloroquine. Moreover, multivariate analysis indicated that disseminated disease (odds ratio (OR): 0.21; 95% confidence interval (CI): 0.08-0.52; P<0.001) and concomitant systemic lupus erythematosus (SLE; OR: 0.06; 95% CI: 0.01-0.49; P = 0.009) were significantly associated with lack of response to hydroxychloroquine. These findings suggest that baseline lupus severity and SLE are predictors of response to hydroxychloroquine. A prospective study is now required to further investigate the relationship between disease activity and response to hydroxychloroquine. This will have the potential to further inform the clinical management of this disfiguring photosensitive disease.
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PMID:Clinical and pharmacogenetic influences on response to hydroxychloroquine in discoid lupus erythematosus: a retrospective cohort study. 2191 70


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