Metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene in mouse liver microsomes and the effect of 2(3)-tert-butyl-4-hydroxy-anisole

Abstract

The metabolism of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP-7,8-diol) was examined using liver microsomes from mice maintained either on a standard laboratory food diet or on a mixture of ground food pellets and 2(3)-tert-butyl-4-hydroxyanisole (BHA, 7.5 g/kg food). Dietary BHA had a statistically significant inhibitory effect both on the formation of polar metabolites of BP-7,8-diol and on the covalent binding of reactive products to calf thymus DNA. When BHA (20 micro M) was added in vitro to the microsomal incubation system, both the metabolism of BP-7,8-diol and the covalent binding of BP-7,8-diol metabolites to DNA, was reduced by approximately 50% using either type of microsomes. The binding of [14C]7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,0,10-tetrahydrobenzo[a]pyrene to calf thymus DNA was not affected by the presence of BHA. The reduced metabolism of BP-7,8-diol in microsomes from BHA-treated mice compared to control was not due to the effect or residual BHA in the microsomal preparation. These results show that BHA acts as a potent inhibitor of the activation of the proximate carcinogen BP-7,8-diol to reactive, DNA-binding products both when administered as a dietary constituent and as an additive to microsomal incubation systems. Both of these properties may be of relevance to the inhibitory effect of BHA on benzo[a]pyrene carcinogenesis.