STEREOSELECTIVE AND REGIOSELECTIVE HYDRATION OF 7-METHYLBENZ[C]ACRIDINE-5,6-OXIDE ENANTIOMERS BY RODENT AND HUMAN MICROSOMAL EPOXIDE HYDROLASES

In the present study, we studied the regioselectivity and stereoselect ivity of human microsomal epoxide hydrolase-catalyzed hydration of the enantiomers of the polycyclic aza-aromatic hydrocarbon K-region oxide , 7-methylbenz[c]acridine-5,6-oxide. We used a human microsomal epoxid e hydrolase cDNA amplified from a liver cDNA library and expressed in COS-7 cells. Comparisons were made with the activities of rat and HLM preparations. The determination of the apparent Michaelis-Menten kinet ic constants revealed that microsomal epoxide hydrolase, regardless of the source, exhibited enantioselectivity, with the 5S,6R-oxide being the preferred substrate. Regioselectivity of hydration for each stereo isomer was determined. Expressed human microsomal epoxide hydrolase an d HLM catalyzed the attack of water predominantly (similar to 96%) at C-5 of the 5R,6S-oxide, whereas 5S,6R-oxide was attacked less selectiv ely (similar to 60% at C-5). These results are discussed in the contex t of available literature on the regioselectivity and stereoselectivit y of rat and rabbit microsomal epoxide hydrolase and represents the fi rst examination of human microsomal epoxide hydrolase regarding its re gioselectivity and stereoselectivity of hydration.