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)

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

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

There is ample evidence that the human acetylator phenotypes are associated with drug induced phenomena. It is principally the slow acetylators who exhibit toxic adverse effects because of their relative inability to detoxify the original drug compounds. In rare instances, however, it is the rapid acetylators who are at a disadvantage. In the matter of association of spontaneous disease with either acetylator phenotype, there are two groups of disorders to consider. First, disorders in which carcinogenic amines are known to be an aetiological factor. This is because these amines are substrates for the polymorphic N-acetyltransferase activity and hence there is a possible rational basis for searching for an association. Secondly, other disorders where searches for associations are based more on hunches. In the first group there is a definite statistical association between cancer of the bladder and the slow acetylator phenotype. In prevalence studies the slow phenotype is 39% more associated with bladder cancer than is the rapid phenotype. On the basis of the evidence now available it is not possible to say whether this association is because slow acetylators develop the disease more frequently or whether they survive longer. In the second group the relevant studies show (1) a greatly increased prevalence of slow acetylators in Gilbert's disease; (2) a confirmed association between the rapid acetylator phenotype and diabetes; (3) a possible association between the rapid acetylator phenotype and breast cancer; (4) a possible association between the slow acetylator phenotype and leprosy in Chinese patients; (5) an earlier age of onset of thyrotoxicosis (Graves' disease) in slow acetylators than in rapid acetylators; (6) no evidence of an association between either phenotype and spontaneous systemic lupus erythematosus.
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PMID:Survey of the human acetylator polymorphism in spontaneous disorders. 638 23

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

1-Hydrazinophthalazine [hydralazine (HDZ)] is a hydrazine derivative that is a direct acting vasodilator effective in the treatment of essential hypertension. HDZ is biotransformed by the phase II conjugation enzyme N-acetyltransferase (NAT) forming acetyl HDZ, which spontaneously cyclized to the stable product 3-methyl-s-triazolo- [3,4-alpha]-phthalazine (MTP). Therapeutic use of HDZ has resulted in adverse side effects, specifically a drug-induced systemic lupus erythematosus. Slow acetylators are more likely than rapid acetylators to develop this toxicity. Bacteria expressing different levels of NAT were used to test the hypothesis that acetylation of HDZ decreases its mutagenic potential. The variation in NAT activities was confirmed by incubating bacterial cultures with HDZ, and the formation of MTP was monitored by HPLC. At 1.0 mg/ml HDZ, YG1029 (NAT overexpresser) produced 5.3 times the amount of MTP as TA100 (normal NAT expresser), and this production was linear for 20 hr. In the Salmonella mutagenesis assay, HDZ produced a dose- and strain-dependent increase in the number of revertants observed. Exposure to 4 mg HDZ/plate resulted in 1000 revertants in the overexpressing strain, YG1029, whereas both TA100 and TA100/1,8DNP6, which express normal levels and lack the NAT protein respectively, produced 1600 revertants. Colony hybridization analysis using probes for each of the six possible TA100 reverting mutations was performed to determine the nature of the mutations. The G:C to T:A transversion was the only mutation whose frequency was increased significantly by HDZ. Fifty-four percent of the induced vs. 25% of the spontaneous mutations were C to A transversions.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylation and its role in the mutagenicity of the antihypertensive agent hydralazine. 758 31

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

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