Therapeutic Lessons from Pharmacogenetics
Authors: Elliot S. Vesell
Journal: Annals of Internal Medicine (1997)

Editorials15 April 1997Therapeutic Lessons from PharmacogeneticsElliot S. Vesell, MD, ScDElliot S. Vesell, MD, ScDPennsylvania State University College of Medicine Hershey, PA 17033-0850Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-126-8-199704150-00012 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Like many other drugs, mercaptopurine and azathioprine are associated with low therapeutic indices; large interindividual variations in their metabolism; and pharmacokinetic perturbation by numerous host factors, including genetic variation. Pharmacogenetics is the exploration of genetically determined alterations in a drug's usual metabolic pathway. Such alterations are often associated with the accumulation and toxicity of a drug and with shifts to different pathways that have toxic intermediates. The paper in this issue by Yates and colleagues [1] on the molecular diagnosis of thiopurine S-methyltransferase (TPM) deficiency as a genetic basis for mercaptopurine and azathioprine toxicity provides an opportunity to discuss several ...References1. Yates CR, Krynetski EY, Loennechen T, Fessing MY, Tai HL, Pui CH, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-14. Google Scholar2. Weinshilboum RM, Vesell ES, eds. Human pharmacogenetics and new directions in pharmacogenetics. Federation Proceedings. 1984; 43:2295-347. Google Scholar3. Kalow W, ed. Pharmacogenetics of Drug Metabolism. International Encyclopedia of Pharmacology and Therapeutics. Oxford: Pergamon Pr; 1992:1-888. Google Scholar4. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980; 32:651-62. 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Vesell ES. Pharmacogenetics: multiple interactions between genes and environment as determinants of drug response. Am J Med. 1979; 66:183-7. Google Scholar14. Szumlanski CL, Weinshilboum RM. Sulphasalazine inhibition of thiopurine methyltransferase: possible mechanism for interaction with 6-mercaptopurine and azathioprine. Br J Clin Pharmacol. 1995; 39:456-9. Google Scholar15. Lennard L, Lilleyman JS, Van Loon J, Weinshilboum RM. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990; 336:225-9. Google Scholar16. Klemetsdal B, Straume B, Wist E, Aarbakke J. Identification of factors regulating thiopurine methyltransferase activity in a Norwegian population. Eur J Clin Pharmacol. 1993; 44:147-52. Google Scholar17. Pacifici GM, Romiti P, Giuliani L, Rane A. Thiopurine methyltransferase in humans: development and tissue distribution. Dev Pharmacol Ther. 1991; 17:16-23. Google Scholar18. Pazmino PA, Sladek SL, Weinshilboum RM. Thio S-methylation in uremia: erythrocyte enzyme activities and plasma inhibitors. Clin Pharmacol Ther. 1980; 20:356-67. Google Scholar19. Jones CD, Smart C, Titus A, Blyden G, Dorvil M, Nwadike N. Thiopurine methyltransferase activity in a sample population of black subjects in Florida. Clin Pharmacol Ther. 1993; 53:348-53. Google Scholar20. McLeod HL, Lin JS, Scott EP, Pui CH, Evans WE. Thiopurine methyltransferase activity in American white subjects and black subjects. Clin Pharmacol Ther. 1994; 55:15-20. Google Scholar Author, Article, and Disclosure InformationAuthors: Elliot S. Vesell, MD, ScDAffiliations: Pennsylvania State University College of Medicine Hershey, PA 17033-0850Corresponding Author: Elliot S. Vesell, MD, ScD, Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033-0850.Corresponding Author: Elliot S. Vesell, MD, ScD, Pennsylvania State University College of Medicine, PO Box 850, Hershey, PA 17033-0850. 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