Methylation pharmacogenetics: Thiopurine methyltransferase as a model system

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Abstract

1. Methyl conjugation is an important pathway in the biotransformation of many drugs and xenobiotic compounds. 'Pharmacogenetic' variation exists in the activities of many methyltransferase enzymes, and experiments with the drug-metabolizing enzyme thiopurine methyltransferase (TPMT) offer a model for one approach that has proven useful in the study of methyltransferase pharmacogenetics. 2. TPMT catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. This enzyme activity is present in the human red blood cell (RBC), and RBC TPMT activity is controlled by a common genetic polymorphism that regulates also the enzyme activity in all other human tissues that have been studied. 3. Subjects with inherited low levels of TPMT activity are at increased risk for thiopurine drug-induced myelotoxicity, while patients with high TPMT activities may be 'undertreated' with these drugs. 4. TPMT activity in tissue from selected strains of inbred mice also is regulated by a genetic polymorphism. These mice provide an animal model for use in the study of pharmacological or toxicological consequences of inherited differences in TPMT activity. 4. Other methyltransferase enzymes including thiol methyltransferase, catechol O-methyltransferase, and histamine N-methyltransferase also are present in the human RBC, are regulated by inheritance, and are responsible for individual variation in drug metabolism. Enhanced understanding of the pharmacogenetics of methylation may make it possible to understand and predict individual variation in the biotransformation toxicity and therapeutic effect of compounds that undergo methyl conjugation.

Original languageEnglish (US)
Pages (from-to)1055-1071
Number of pages17
JournalXenobiotica
Volume22
Issue number9-10
DOIs
StatePublished - 1992

Fingerprint

thiopurine methyltransferase
Methylation
Pharmacogenetics
Methyltransferases
Pharmaceutical Preparations
Enzymes
Blood
Erythrocytes
thiol S-methyltransferase
Enzyme activity
Genetic Polymorphisms
Biotransformation
Polymorphism
Histamine N-Methyltransferase
Cells
Tissue
Catechol O-Methyltransferase
6-Mercaptopurine
Inbred Strains Mice
Therapeutic Uses

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology
  • Biochemistry
  • Health, Toxicology and Mutagenesis
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Methylation pharmacogenetics : Thiopurine methyltransferase as a model system. / Weinshilboum, Richard M.

In: Xenobiotica, Vol. 22, No. 9-10, 1992, p. 1055-1071.

Research output: Contribution to journalArticle

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