Thiol methylation pharmacogenetics: Heritability of human erythrocyte thiol methyltransferase activity

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Abstract
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 1st 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 1st-degree relatives in 47 randomly selected families. The frequency distribution of enzyme activities was unimodal, with a 5-fold variation within .+-. 2 SD. 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 1st-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. Sibling-sibling (S-S), parent-offspring (P-O) and midparent (average of 2 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. Apparently inheritance was the primary factor regulating the 5-fold variation in RBC TMT activity.