Thiol methylation pharmacogenetics: Heritability of human erythrocyte thiol methyltransferase activity

Richard A. Keith, Jon Van Loon, Luanne F. Wussow, Richard M. Weinshilboum

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26 Scopus citations


Thiol methylation of aliphatic sulfhydryl drugs is catalyzed by thiol methyltransferase (TMT), an enzyme activity that can be measured in the human erythrocyte (RBC) membrane. As a first step toward determining the possible role of inheritance in the regulation of individual variations in the S-methylation of drugs in man, the heritability of human RBC membrane TMT activity was determined. RBC TMT activity was measured in blood samples from 231 first-degree relatives in 47 randomly selected families. The frequency distribution of enzyme activities was unimodal, with a fivefold variation within ±2 SDs. RBC TMT activity did not correlate with either age or sex. Heritability in the "narrow" sense (h2) was estimated by comparing correlations of RBC TMT activities in first-degree relatives with theoretical values expected for a trait under total additive genetic control. The correlation between RBC TMT activities in mothers and fathers in these families was only 0.04, a finding that made shared environment a less likely explanation for significant correlations among other family members. However, sibling-sibling (S-S), parent-offspring (P-O), and midparent (average of two parental values) -offspring (M-O) correlations were 0.49, 0.49, and 0.69. Theoretical expected values for a trait with a heritability of 1.0 (100%), for these same correlations would be 0.5, 0.5, and 0.71. Estimates of h2 calculated from the observed correlations were 0.98 (S-S), 0.98 (P-O), and 0.98 (M-O). None of the calculated values for heritability differed significantly from the theoretical maximum value of 1.0. These results suggested that inheritance was the primary factor- regulating the fivefold variation in RBC TMT activity.

Original languageEnglish (US)
Pages (from-to)521-528
Number of pages8
JournalClinical pharmacology and therapeutics
Issue number4
StatePublished - Oct 1983

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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