Short time interval effects of butylated hydroxyanisole on the metabolism of benzo[a]pyrene

Within 4 hr after administration of butylated hydroxyanisole (BHA) by p.o. intubation, marked changes in the microsomal metabolism of benzo[a]pyrene (BP) occur. Liver microsomes isolated from female A/HeJ mice under these conditions show a depression of BP metabolism by more than 16%. The effects on individual metabolites as determined by high-pressure liquid chromatography differ. Relative increases in 3-hydroxybenzo[a]pyrene and in the dione regions were observed. In contrast, benzo[a]pyrene 4,5 oxide formation was decreased greater than 30%. trans-4,5 Dihydroxy 4,5-dihydrobenzo[a]pyrene underwent a similar decrease while the other two diols, trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and trans-9,10-dihydroxy-9,10-dihydrobenzo[a]pyrene showed no significant alteration. The most profound decrease was in the concentration of metabolites in the very polar region of the chromatogram. The retention times of some of these peaks coincide with those of the hydrolysis products of BP diolepoxides, i.e., tetrols and triols. A reduction in these highly polar metabolites is a good indication that the formation of diolepoxides was inhibited by BHA. Thus, BHA alters microsomal metabolism by diminishing activation reactions leading to the formation of ultimate carcinogenic metabolites and also enhances formation of metabolites of detoxification. Along with the change in BP metabolite pattern, BHA given in vivo induces a different response of microsomes to subsequent in vitro addition of BHA. The capacity of microsomes to undergo rapid changes that overall diminish formation of carcinogenic metabolites could constitute an important protective mechanism.