Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.67 (thiopurine methyltransferase)
 551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polymorphisms have been detected in a variety of xenobiotic-metabolizing enzymes at both the phenotypic and genotypic level. In the case of four enzymes, the cytochrome P450 CYP2D6, glutathione S-transferase mu, N-acetyltransferase 2 and serum cholinesterase, the majority of mutations which give rise to a defective phenotype have now been identified. Another group of enzymes show definite polymorphism at the phenotypic level but the exact genetic mechanisms responsible are not yet clear. These enzymes include the cytochromes P450 CYP1A1, CYP1A2 and a CYP2C form which metabolizes mephenytoin, a flavin-linked monooxygenase (fish-odour syndrome), paraoxonase, UDP-glucuronosyltransferase (Gilbert's syndrome) and thiopurine S-methyltransferase. In the case of a further group of enzymes, there is some evidence for polymorphism at either the phenotypic or genotypic level but this has not been unambiguously demonstrated. Examples of this class include the cytochrome P450 enzymes CYP2A6, CYP2E1, CYP2C9 and CYP3A4, xanthine oxidase, an S-oxidase which metabolizes carbocysteine, epoxide hydrolase, two forms of sulphotransferase and several methyltransferases. The nature of all these polymorphisms and possible polymorphisms is discussed in detail, with particular reference to the effects of this variation on drug metabolism and susceptibility to chemically-induced diseases.
 ...
PMID:Metabolic polymorphisms. 836 90

It is widely claimed that pharmacogenetics may form the basis of 'personalized medicine'. We sought to determine the current utilization of pharmacogenetic testing for drug metabolizing enzymes (DMEs). The hypothesis was that these tests were rarely performed clinically. Questionnaires were sent to 629 individuals representing laboratories, hospitals and universities throughout Australia and New Zealand. The questionnaires asked which facilities performed pharmacogenetic tests for selected DMEs, and details about the tests, if performed. The overall response rate was 81.1% (510/629); three respondents declined to participate. Clinical genotyping and phenotyping tests for DMEs could be performed by 10 (2.0% of 507) and 18 (3.6%) facilities, respectively. The most frequently performed genetic tests were for thiopurine methyltransferase (approximately 400 times in 2003) and pseudocholinesterase (approximately 250 times). The frequency of phenotyping exceeded genotyping by five- and eight-fold, respectively. One centre performed CYP2D6 phenotyping frequently (approximately 4200 times in 2003) for perhexiline. Genotyping and phenotyping tests for other cytochrome P450 enzymes, N-acetyltransferase-2 and dihydropyrimidine dehydrogenase were effectively never undertaken for clinical purposes. Pharmacogenetic tests for DMEs are currently performed rarely in clinical practice, despite repeated claims that they may benefit patient care. The only tests performed with any regularity in Australasia are for thiopurine methyltransferase and pseudocholinesterase, and CYP2D6 phenotyping in one centre for patients on perhexiline. The low clinical utilization reflects a poor evidence base, unestablished clinical relevance and, in the few cases with the strongest rationale, a slow translation to the clinical setting.
 ...
PMID:Pharmacogenetic testing for drug metabolizing enzymes: is it happening in practice? 1586 39

The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
 ...
PMID:Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. 1696 50