Interindividual and Interspecies Variation in Hepatic Microsomal Epoxide Hydrolase Activity: Studies with

Microsomal epoxide hydrolase (HYL1) is a single-gene enzyme responsible for the hydrolysis of epoxides derived from the oxidative metabolism of xenobiotics. Variation in HYL1, there-fore, may be an important determinant of drug toxicity. We have investigated HYL1 enzyme kinetics in six different species in-cluding man, for which a liver bank genotyped for polymor-phisms in exons 3 and 4 of the HYL1 gene was used. Activity was measured by radiochromatography with high specific ac-tivity radiolabeled substrates, cis-stilbene oxide (CSO) and car-bamazepine 1 0,1 1-epoxide (CBZ-E). In addition, naphthalene was used to investigate the hydrolysis of an epoxide (naphtha-lene 1,2-epoxide [N-E]) generated in situ. There was marked species variation in enzyme activity that was substrate depen-dent. CSO was rapidly hydrolyzed by microsomes from all species, the rank order of specific activity being human&gt