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)

An investigation has been conducted on the foreign compound-metabolizing activity of human liver collected fresh from surgery or at autopsy from cadavers 3 to 18 hr old, and the effects of low temperature storage on the foreign compound-metabolizing activity of fresh human liver. The enzyme activities studied were microsomal cytochrome P-450 content, biphenyl 4-hydroxylation, benzo-(a)pyrene metabolism, halothane reduction, and 4-hydroxybiphenyl UDP-glucuronosyl transferase, as well as cytosolic thiopurine methyltransferase, thermostable (TS) phenolsulfotransferase, thermolabile (TL) phenolsulfotransferase, and 5-fluorouracil dehydrogenase. Cadaver liver was a poor source of material for metabolism studies with the majority of the enzymes investigated. There was an 84% decrease in the yield of microsomal protein, a 64% decrease in cytochrome P-450 content per mg of microsomal protein, and a 36% decrease in the biphenyl 4-hydroxylase specific activity in human cadaver liver that was a few hours old. UDP-glucuronosyl transferase showed a 70% decrease, TS phenolsulfotransferase a 84% decrease, TL phenolsulfotransferase a 97% decrease, and thiopurine methyltransferase no significant change in specific activity. The loss of activity for many of these enzymes could be simulated by keeping fresh human liver at the temperature of the body after death. Surgical waste provided a good source of fresh, histologically normal, human liver for metabolism studies. Microsomal cytochrome P-450 content showed a significant increase with the age of the liver donor. Metabolism of benzo(a)pyrene to 3-hydroxybenzo(a)pyrene and benzo(a)pyrene-7,8- and -9,10-diols showed up to 136% higher rates in fresh liver microsomes from female donors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Foreign compound metabolism studies with human liver obtained as surgical waste. Relation to donor characteristics and effects of tissue storage. 290 27

Clinical and other aspects of pharmacogenetics and pharmacogenomics are discussed. Pharmacogenetics is the study of the impact of heritable traits on pharmacology and toxicology. An extension of pharmacogenetics is the discovery that genetic polymorphisms have the potential to affect a drug's action. The interplay of genotype and drug efficacy has been defined as pharmacogenomics. For most drugs, variations in patient response have until recently been considered a result of pharmacokinetic rather than pharmacodynamic differences. However, it now seems that pharmacodynamic variability in humans is large, reproducible, and usually more pronounced than pharmacokinetic variability. Some examples of the impact of pharmacogenomics on pharmacokinetics involve cytochrome P-450 isoenzymes, dihydropyrimidine dehydrogenase, and thiopurine methyltransferase; some examples of the impact on pharmacodynamics involve cholesteryl ester transfer protein, angiotensin-converting enzyme, and serotonin transporter. There are no specific statistical techniques for analyzing data from pharmacogenomic clinical trials. However, a tabulated relationship for the determination of the maximum possible gain in response rate for the highest-responding genotypic subgroup of patients is provided as an aid to determining whether it is worth having a pharmacogenomic strategy for a given drug. Ethical issues in pharmacogenomics tend to be based on the general concern that the ability to diagnose a genetic disorder before any treatment is available does more harm than good to the patient. Pharmacogenomic approaches to drug discovery and delivery have been recognized by FDA. Pharmacogenomics cannot improve the efficacy of a given drug, but it helps in selecting patients who are likely to respond well. Pharmacogenomics provides a view of drug behavior and sensitivity useful to improving the efficacy of drug development and utilization.
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PMID:Clinical trials in pharmacogenetics and pharmacogenomics: methods and applications. 1084 May 30

Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent.
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PMID:Drug monitoring in inflammatory bowel disease: helpful or dispensable? 1978 71