The effects of modulation of microsomal epoxide hydrolase activity on microsome-catalyzed activation of benzo[alpha]pyrene and its covalent binding to DNA.
The effects of modulation of microsomal epoxide hydrolase activity on the binding of calf thymus DNA of benzo[alpha]pyrene metabolically activated by rat liver microsomes were investigated. In systems where microsomal epoxide hydrolase levels were not manipulated, 2 major bound species, one derived from 9-hydroxybenzo[alpha]pyrene and the other derived from benzo[alpha]pyrene 7,8-dihydrodiol, were found in approximately equivalent amounts. When epoxide hydrolase levels were increased, either by addition in vitro of purified enzyme or by induction in vivo by trans-stilbene oxide, the binding of the benzo[alpha]pyrene 7,8-dihydrodiol product was increased, while the binding of the 9-hydroxybenzo[alpha]pyrene product was practically eliminated. When microsomal epoxide hydrolase activity was decreased by selective inhibition with low concentrations of 1,1,1-trichloropropene 2,3-oxide, the binding of the species derived from 9-hydroxybenzo[alpha]pyrene was increased several-fold, while that of the species derived from benzo[alpha]pyrene 7,8-dihydrodiol was greatly decreased. The results indicate that the binding species derived from 9-hydroxybenzo[alpha]pyrene is formed through a metabolic pathway leading to an epoxide which is a substrate of microsomal epoxide hydrolase and that microsomal epoxide hydrolase is important in regulating the pattern of binding of individual microsomally-formed benzo[alpha]pyrene metabolites to DNA.
D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism*; D001711:Biotransformation; D004247:DNA / Q000378:metabolism*; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats
D001580:Benzopyrenes; D008748:Methylcholanthrene; D004247:DNA; D004851:Epoxide Hydrolases