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)

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

The clinical significance of two separate genetic polymorphisms which alter drug metabolism, acetylation and oxidation is discussed, and methods of phenotyping for both acetylator and polymorphic oxidation status are reviewed. Particular reference is made to the dapsone method, which provides a simple means of distinguishing fast and slow - and possibly intermediate - acetylators, and to the sparteine method which allows a clear separation of oxidation phenotypes. Although acetylation polymorphism has been known for some time, definite indications for phenotyping are few. It is doubtful whether acetylator phenotype makes a significant difference to the outcome in most isoniazid treatment regimens, and peripheral neuropathy from isoniazid in slow acetylators is easily overcome by pyridoxine administration. However, in comparison with rapid acetylators, slow acetylators receiving isoniazid have an increased susceptibility to phenytoin toxicity, and perhaps also to carbamazepine toxicity. It is also possible that rapid acetylators receiving isoniazid attain higher serum fluoride concentrations from enflurane and similar anaesthetics than do similarly treated slow acetylators. Thus, when drug interactions of these types are suspected, phenotyping for acetylator status may be advisable. If routine monitoring of serum procainamide and N-acetylprocainamide concentrations is practised, phenotyping of subjects prior to therapy with these agents should not be necessary. Although acetylator phenotype influences serum concentrations of hydralazine, when this drug is given in combination with other drugs acetylator phenotype has not been shown to influence the therapeutic response. Slow acetylator phenotype along with female gender and the presence of HLA-DR antigens appear to be risk factors in the development of hydralazine-induced systemic lupus erythematosus (SLE). Determination of acetylator phenotype may therefore help determine susceptibility to this adverse reaction. In the case of sulphasalazine, adult slow acetylators require a lower daily dose of the drug than fast acetylators in order to maintain ulcerative colitis in remission without significant side effects. It is therefore advisable to determine acetylator phenotype prior to sulphasalazine therapy. Work on the association of acetylation polymorphism with various disease states is also reviewed. It is possible that a higher incidence of bladder cancer is associated with slow acetylation phenotype - especially in individuals exposed to high levels of arylamines. The question as to whether idiopathic SLE is more common in slow acetylators remains unresolved. There appears to be no difference between fa
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PMID:Genetically determined variability in acetylation and oxidation. Therapeutic implications. 285 77