Genetic control of interindividual variations in the inducibility of aryl hydrocarbon hydroxylase in cultured human lymphocytes

Abstract

Interindividual and intraindividual variations in aryl hydrocarbon hydroxylase (AHH) induction by 3-methylcholanthrene were studied in cultured lymphocytes from normal adult volunteers. Using eight pairs of monozygotic and eight pairs of dizygotic twins, we examined to what extent these variations are controlled by heritable factors and whether AHH inducibility correlations in an individual with the plasma half-lives of three drugs. Substantial overestimation of the induction ratio (fold inducibility) may occur if the nonlinearity of the assay standard curve is not considered. Fold inducibility remains relatively constant for an individual, but large intraindividual variations occur in absolute "control" and "induced" AHH activities. Fetal calf serum may contain inducers of AHH activity that vary with the particular lot of serum, thereby rendering the apparent induction ratio an imprecise indicator of genetic susceptibility to induction by 3-methylcholanthrene. The index of heritability for AHH fold inducibility in twins studied with different lots of fetal calf serum (0.80) or with a single lot of fetal calf serum (0.77) suggests nonetheless that genetic rather than environmental factors are mainly responsible for interindividual variations in AHH inducibility by 3-methylcholanthrene in human lymphocytes. In these twins a significant but poor correlation (r=-0.551; 0.03 less than p less than 0.05) occurs between AHH inducibility in culture and the plasma antipyring half-life, but not between AHH inducibility and phenylbutazone or bishdroxycoumarin half-lives.