HUMAN HEPATIC-MICROSOMAL EPOXIDE HYDROLASE - COMPARATIVE-ANALYSIS OF POLYMORPHIC EXPRESSION

Interindividual variation in the expression of human microsomal epoxid e hydrolase (mEH) may be an important risk factor for chemically induc ed toxicities, including cancer and teratogenesis. In this study, phen otypic variability and mEH genetic polymorphisms were examined in a ba nk of 40 transplant-quality human liver samples. Immunochemically dete rmined protein content, enzymatic activities, polymorphic amino acids, as well as mEH RNA levels were evaluated in parallel. Enzymatic activ ity was assessed using (+/-)-benzo[a]pyrene-4,5-epoxide at 2 substrate concentrations. The relative hydrolyzing activities obtained using sa turating substrate levels were highly correlated (r = 0.85) with resul ts derived from limiting substrate concentrations and exhibit approxim ately an 8-fold range in activity levels across the panel of 40 liver samples. mEH enzyme activity also demonstrated strong correlation (r g reater than or equal to 0.74) with an 8.4-fold variation determined fo r mEH protein content within the same samples. However, these protein/ activity measurements were poorly correlated (r less than or equal to 0.23) with mEH RNA levels, which exhibited a 49-fold variation. Two co mmon polymorphic amino acid loci in the mEH protein did not exclusivel y account for variation in enzymatic activity, although this conclusio n is confounded by heterozygousity in the samples. These data demonstr ate the extent of hepatic mEH functional variability in well-preserved human tissues and suggest that polymorphism of mEH protein expression is regulated in part by posttranscriptional controls, which may inclu de nonstructural regulatory regions of the mEH transcript. (C) 1997 Ac ademic Press