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)

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.
 ...
PMID:Methylation pharmacogenetics: thiopurine methyltransferase as a model system. 144 97

1. The aim was to investigate the possibility of interindividual variability of histamine N-methyltransferase (HNMT) in the human liver and renal cortex. The activity of HNMT was measured in 99 specimens of the human liver and in 75 specimens of the renal cortex. 2. In the liver the activity of HNMT was positively skewed. It ranged 2.9-fold with a median of 1.72 pmol/min/mg. In the renal cortex the activity of HNMT was normally distributed and ranged 2.6-fold with a mean and coefficient of variation of 1.35 pmol/min/mg and 21%, respectively. 3. The activities of catechol methyltransferase and thiopurine methyltransferase were measured in the renal cortex and any correlations with HNMT activity were assessed. There was a weak but significant correlation (r = 0.294, p = 0.010) between HNMT and catechol methyltransferase activities whereas HNMT activity was not correlated with thiopurine methyltransferase activity. 4. These results are consistent with the view that HNMT is well expressed in the human liver and renal cortex and that it varies among subjects.
 ...
PMID:Interindividual variability of histamine N-methyltransferase in the human liver and kidney. 966 80

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
 ...
PMID:Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. 1033 Oct 75