Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.
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PMID:Drug-induced immune-complex disease. 252 48

A/J mice are proposed as a model of the human lupus diathesis since we previously determined that they express a slow acetyltor phenotype while others showed them to have a predisposition to develop spontaneous and drug-induced antinuclear antibodies. A/J mice were mated with C57BL/6J mice, a rapid acetylator phenotype which is relatively resistant to spontaneous and drug-induced antinuclear antibodies, to assess the importance of slow acetylator status as a component of the lupus diathesis. Procainamide, a potent inducer of antinuclear antibodies, was acetylated to a lesser degree by A/J mice than by C57BL/6J mice. This difference, detectable by in vitro assay but not by urinary levels of acetylated drug, represents a genetic polymorphism which can be detected in F2 and backcross progency of these two strains. We confirmed that A/J mice have a higher incidence of spontaneous antinuclear antibodies than C57BL/6J mice and that in A/J mice these antibodies can be induced by oral procainamide (6 g/l of drinking water for 37 weeks); procainamide tended to suppress antinuclear antibody formation in C57BL/6J mice, however. Rapid and slow acetylators among F2 and backcross populations were identified by a test for N-acetyltransferase activity in blood hemolysates. These two groups together with their respective rapid and slow acetylator parents were compared in respect to incidence of antinuclear antibodies. Slow acetylator phenotypes among F2 and backcross mice were predisposed to high titers of antinuclear antibodies like the slow acetyltor A/J strain. However, long-term exposure to procainamide suppressed antinuclear antibody formation as was found in the rapid acetylator C57BL/6J strain. Thus, the ability to N-acetylate procainamide is not the sole factor controlling the ability of this drug to induce antinuclear antibodies.
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PMID:Antinuclear antibodies related to acetylator phenotype in mice. 697 Aug 9

Human arylamine N-acetyltransferase (NAT) activity is determined by two distinct genes, NAT1 and NAT2, and the classical acetylation polymorphism in NAT2 has been associated with a variety of disorders, including lupus erythematosus and arylamine induced cancers. Over 50% of the white population exhibit a slow acetylator phenotype. The genetic basis of the defect has been identified and several DNA based assays are available for genotyping studies. We present here a simplified, rapid PCR based assay for the identification of the major slow acetylator genotypes and validate it using isoniazid as probe drug. This assay was 100% predictive of phenotype. The three genotypes (homozygous mutated, heterozygous, and homozygous rapid) corresponded to a trimodal distribution of Ac-INH/INH metabolic ratios (slow, intermediate, and rapid) without overlapping.
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PMID:A simplified assay for the arylamine N-acetyltransferase 2 polymorphism validated by phenotyping with isoniazid. 932 64

Polymorphic N-acetyltransferase (NAT2) is involved in the metabolism of several compounds relevant in pharmacology or toxicology, with diverse clinical consequences. Inter-ethnic variations in distribution of the acetylation phenotype are significant. The caffeine test is most often used to assess the acetylation phenotype and to identify rapid and slow acetylators. The NAT2 phenotype could account for the increased risk of certain side effects in slow acetylators treated with isoniazid (particularly peripheral neuropathies and lupus erythematosus), although therapeutic efficacy seems to be independent of the acetylation status. Hypersensibility reactions with sulfonamides (including Lyell and Stevens-Johnson syndromes) are more frequent in slow acetylators, who also show poor tolerance to sulfasalazine and dapsone. In contrast, myelotoxicity induced by amonafide is more frequent in rapid acetylators, probably because of increased production of a toxic metabolite of the drug. In carcinogenesis, NAT2 may play a protective role against bladder cancer, although studies have shown contradictory results. Slow acetylators may have a risk of developing primitive liver cancer. For lung cancer, data are not conclusive, but slow acetylation status may predispose to mesothelioma in subjects exposed to asbestos. No relation has been found between acetylation phenotype and breast cancer. Contradictory results were reported on its role in colorectal cancer. Non-smoking type 1 diabetics may be at increased risk of nephropathy if they are rapid acetylators. Parkinson's disease may be more frequent among slow acetylators, but again, data have shown contradictory results. Finally, a poor acetylator phenotype may predispose to atopic diseases.
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PMID:[Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism]. 1261 Nov 96

Arylamine N-acetyltransferases (NATs) catalyse the N-acetylation of arylamines, arylhydroxylamines and arylhydrazines with the acetyl group being transferred from acetylCoenzyme A. As a result of many recent advances in NAT research there have been many recent reviews and the present paper gives a flavour of the excitement in the field. The NATs, which are cytosolic, were early examples of pharmacogenetic variation. Polymorphism in isoniazid inactivation resulting in slow acetylation was subsequently found to be due to SNPs in the gene encoding the human isoenzyme NAT2. There are two polymorphic genes (NAT1 and NAT2) encoded with a third pseudogene (NATP) at human 8p21.3. The gene structure of NAT1 and NAT2, with a single (NAT2) or multiple (NAT1) distant non-coding exons showing tissue specific splicing, opens possibilities for effects of polymorphisms outside the single coding exon. In humans, the substrate specificities of NAT1 and NAT2 are overlapping but distinct. The NAT2 isoenzyme, predominantly in liver and gut, acetylates sulphamethazine and arylhydrazine compounds. Slow acetylators are at increased risk of toxicity, e.g. isoniazid induced neurotoxicity and hydralazine-induced lupus. The human NAT1 isoenzyme is also polymorphic. It is expressed in many tissues, particularly in oestrogen receptor positive breast cancers. Human NAT1 has an endogenous role in acetylation of a folate catabolite with in vivo evidence from transgenic mice lacking the equivalent gene. For nomenclature see http://louisville.edu/medschool/pharmacology/NAT.html, the website maintained by David Hein. NAT homologues have been identified by bioinformatics analyses in zebrafish and these sequences are described, although the proteins have not yet been characterized. The first NAT crystallographic structure from Salmonella typhimurium identified the mechanism of acetyl transfer via a catalytic triad of Cys, His and Asp residues each essential for activity in all NATs. NATs from mycobacteria aided in identifying the substrate binding site and the acetylCoA binding pocket. Studies on the eukaryotic enzymes by NMR and crystallography have facilitated understanding substrate specificities of human NAT1 (5-aminosalicylate and p-aminobenzoic acid) and human NAT2 (sulphamethazine). The effect of "slow acetylator" SNPs in the coding region predominantly act through creating unstable protein that aggregates intracellularly prior to ubiquitination and degradation.
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PMID:Arylamine N-acetyltransferases: structural and functional implications of polymorphisms. 1885 12

Isoniazid (INH) treatment can cause serious liver injury and autoimmunity. There are now several lines of evidence that INH-induced liver injury is immune mediated, but this type of liver injury has not been reproduced in animals, possibly because immune tolerance is the dominant response of the liver. In this study, we immunized mice with isonicotinic acid (INA)-modified proteins and Freund's adjuvant, which led to mild experimental autoimmune hepatitis (EAH) with an increase in cells staining positive for F4/80, CD11b, CD8, CD4, CD45R, and KI67. We expected that subsequent treatment of mice with oral INH would lead to more serious immune-mediated liver injury, but paradoxically it markedly attenuated the EAH caused by immunization with INA-modified hepatic proteins. In addition, patients of the slow acetylator phenotype are at increased risk of INH-induced liver injury. Treatment of arylamine N-acetyltransferase-deficient Nat1/2(-/-) mice with INH for up to 5 weeks produced mild increases in glutamate and sorbitol dehydrogenase activities, but not severe liver injury. Female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days developed steatosis, an increase in Oil Red O staining, and abnormal mitochondrial morphology in the liver. A decrease in M1 and an increase in M2a and M2b macrophages was observed in female Nat1/2(-/-) mice treated with INH for 1, 3, or 7 days; these changes returned to baseline levels by day 35. These data indicate that INH has immunosuppressive effects, even though it is also known to induce autoantibody production and a lupus-like autoimmune syndrome in humans.
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PMID:Paradoxical attenuation of autoimmune hepatitis by oral isoniazid in wild-type and N-acetyltransferase-deficient mice. 2462 63