Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives

L. C. Woodson, M. M. Ames, C. D. Selassie, C. Hansch, Richard M Weinshilboum

Research output: Contribution to journalArticle

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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 was found to inhibit purified human kidney TPMT. Concentrations required to inhibit TPMT by 50% ranged from 20 μM for 3,4-dimethoxy-5-hydroxybenzoic acid to 2.1 mM for acetylsalicylic 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, π', related to lipophilicity. Several nonheterocyclic aromatic thiol compounds, including thiophenol and thiosalicylic acid, were discovered to be substrates for TPMT. Apparent K(m) constants for some of these aromatic thiol compounds were in the nanomolar range, several orders of magnitude lower than those of the thiopurines and thiopyrimidines previously thought to be the only substrates for TPMT. These observations suggested that '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.

Original languageEnglish (US)
Pages (from-to)471-478
Number of pages8
JournalMolecular Pharmacology
Volume24
Issue number3
StatePublished - 1983

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thiopurine methyltransferase
Benzoic Acid
Sulfhydryl Compounds
thiol S-methyltransferase
Enzymes
Pharmaceutical Preparations
6-Mercaptopurine
S-Adenosylmethionine
Quantitative Structure-Activity Relationship
Drug and Narcotic Control
Clinical Medicine
Structure-Activity Relationship
Hydroxyl Radical
Methylation
Aspirin
Names

ASJC Scopus subject areas

  • Pharmacology

Cite this

Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. / Woodson, L. C.; Ames, M. M.; Selassie, C. D.; Hansch, C.; Weinshilboum, Richard M.

In: Molecular Pharmacology, Vol. 24, No. 3, 1983, p. 471-478.

Research output: Contribution to journalArticle

Woodson, L. C. ; Ames, M. M. ; Selassie, C. D. ; Hansch, C. ; Weinshilboum, Richard M. / Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. In: Molecular Pharmacology. 1983 ; Vol. 24, No. 3. pp. 471-478.
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