THIOPURINE METHYLTRANSFERASE - AROMATIC THIOL SUBSTRATES AND INHIBITION BY BENZOIC-ACID DERIVATIVES

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 24  (3) , 471-478
Abstract
Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine and thiopyrimidine drugs. If potent TPMT inhibitors were available, studies of the regulation and properties of this drug-metabolizing enzyme would be facilitated. Each of a series of benzoic acid derivatives tested inhibited purified human kidney TPMT. Concentrations required to inhibit TPMT by 50% ranged from 20 .mu.M for 3,4-dimethoxy-5-hydroxybenzoic acid to 2.1 mM for acetylsalicyclic acid. Inhibition was noncompetitive or mixed with respect to both S-adenosyl-L-methionine, the methyl donor for the enzyme, and 6-mercaptopurine, the methyl acceptor substrate. Preliminary structure-activity relationship analysis demonstrated that the benzoic acid structure was important for inhibitory activity, and that inhibition was enhanced by the addition of methoxy and/or phenolic hydroxyl groups to the ring. Quantitative structure-activity relationship analysis performed with additional benzoic acid derivatives showed that inhibitory activity could be modeled well by an equation that included the normal Hammett constant and a parameter, .pi.'', related to lipophilicity. Several nonheterocyclic aromatic thiol compounds, including thiophenol and thiosalicylic acid, were discovered to be substrates for TPMT. Apparent Km constants for some of these aromatic thiol compounds were in the nmol range, several orders of magnitude lower than those of the thiopurines and thiopyrimidines previously thought to be the only substrates for TPMT. Aryl thiol methyltransferase might be a better name than thiopurine methyltransferase for this enzyme. Discovery of new classes of inhibitors and substrates for this important drug-metabolizing enzyme has implications for drug metabolism research and for clinical medicine.