Human erythrocyte membrane thiol methyltransferase. S-methylation of captopril, N-acetylcysteine, and 7α-thio-spirolactone

R. A. Keith, I. Jardine, A. Kerremans, Richard M Weinshilboum

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Thiol methylation is an important pathway in the biotransformation of sulfhydryl drugs such as captopril. Human red blood cell (RBC) membranes contain a thiol methyltransferase (TMT) activity that catalyzes the S-methylation of 2-mercaptoethanol (2-ME). These experiments were performed to determine whether human RBC membranes contained enzymes that could catalyze the S-methylation of thiol drugs, and, if so, to determine whether those enzymes were similar to the RBC membrane TMT that catalyzes the S-methylation of 2-ME. Human RBC membranes were able to catalyze the methylation of captopril, N-acetylcysteine, and 7α-thio-spirolactone, a sulfhydryl metabolite of spironolactone. Those activities and 2-ME TMT were similar with respect to subcellular distribution, inhibitor sensitivity, and thermal stablity. When activities of the methyltransferase enzymes for 2-ME and for the three thiol drugs were measured in RBC membranes from 19 individual subjects, there were highly significant correlations among all four activities (r > 0.96 for all comparisons). These observations suggested either that a single enzyme in the human RBC membrane catalyzed the S-methylation of all of these compounds, or, less likely, that these were four separate activities regulated in parallel with similar properties. Experiments were then performed to identify the products of the enzyme reactions. The product of the reaction performed with 7α-thio-spirolactone was the expected S-methyl derivative, 7α-thiomethyl-spirolactone. However, it was found that lipophilic conjugates of the S-methyl derivatives of captopril and N-acetylcysteine were formed during the in vitro enzyme reaction. The lipophilic conjugate of captopril was identified as the ethyl ester of the S-methyl metabolite. It remains to be determined whether lipophilic conjugates of the S-methyl metabolites of these and other carboxylic acid sulfhydryl drugs may be formed in vivo.

Original languageEnglish (US)
Pages (from-to)717-724
Number of pages8
JournalDrug Metabolism and Disposition
Volume12
Issue number6
StatePublished - 1984

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thiol S-methyltransferase
Spironolactone
Methylation
Captopril
Acetylcysteine
Erythrocyte Membrane
Cell membranes
Blood
Mercaptoethanol
Erythrocytes
Cell Membrane
Membranes
Enzymes
Metabolites
Sulfhydryl Compounds
Pharmaceutical Preparations
Derivatives
Methyltransferases
Biotransformation
Carboxylic Acids

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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Human erythrocyte membrane thiol methyltransferase. S-methylation of captopril, N-acetylcysteine, and 7α-thio-spirolactone. / Keith, R. A.; Jardine, I.; Kerremans, A.; Weinshilboum, Richard M.

In: Drug Metabolism and Disposition, Vol. 12, No. 6, 1984, p. 717-724.

Research output: Contribution to journalArticle

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abstract = "Thiol methylation is an important pathway in the biotransformation of sulfhydryl drugs such as captopril. Human red blood cell (RBC) membranes contain a thiol methyltransferase (TMT) activity that catalyzes the S-methylation of 2-mercaptoethanol (2-ME). These experiments were performed to determine whether human RBC membranes contained enzymes that could catalyze the S-methylation of thiol drugs, and, if so, to determine whether those enzymes were similar to the RBC membrane TMT that catalyzes the S-methylation of 2-ME. Human RBC membranes were able to catalyze the methylation of captopril, N-acetylcysteine, and 7α-thio-spirolactone, a sulfhydryl metabolite of spironolactone. Those activities and 2-ME TMT were similar with respect to subcellular distribution, inhibitor sensitivity, and thermal stablity. When activities of the methyltransferase enzymes for 2-ME and for the three thiol drugs were measured in RBC membranes from 19 individual subjects, there were highly significant correlations among all four activities (r > 0.96 for all comparisons). These observations suggested either that a single enzyme in the human RBC membrane catalyzed the S-methylation of all of these compounds, or, less likely, that these were four separate activities regulated in parallel with similar properties. Experiments were then performed to identify the products of the enzyme reactions. The product of the reaction performed with 7α-thio-spirolactone was the expected S-methyl derivative, 7α-thiomethyl-spirolactone. However, it was found that lipophilic conjugates of the S-methyl derivatives of captopril and N-acetylcysteine were formed during the in vitro enzyme reaction. The lipophilic conjugate of captopril was identified as the ethyl ester of the S-methyl metabolite. It remains to be determined whether lipophilic conjugates of the S-methyl metabolites of these and other carboxylic acid sulfhydryl drugs may be formed in vivo.",
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