Effects of butylated hydroxyanisole on the metabolism of benzo(a)pyrene by mouse lung microsomes

Abstract

Butylated hydroxyanisole (BHA) is a commonly used food additive with demonstrated inhibitory action against chemical carcinogenesis in animals. In order to elucidate the mechanism of the anticarcinogenic action, the effects of BHA on benzo(a)pyrene (BP) metabolism were studied with lung microsomes from female mice. BHA treatment (0.5% in the diet for 7 days) inhibited BP metabolism and altered the ratios among different metabolites as analyzed by high-performance liquid chromatography. The treatment reduced the metabolic formation of 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene, but not the production of 3-hydroxybenzo(a)pyrene and trans-4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene. Since the gross microsomal cytochrome P-450 content was not significantly affected by the treatment, the change of regioselectivity in BP metabolism was probably due to the alteration of cytochrome P-450 isozyme composition by dietary BHA. General and regioselective inhibition of BP metabolism was also observed when BHA was added to the lung microsomal incubation mixture. The formation of 9,10-dihydroxy-9,10-dihydrobenzo(a)pyrene and 9-hydroxybenzo-(a)pyrene was inhibited more severely than that of trans-4,5-dihydroxy-4,5-dihydrobenzo(a)pyrene and trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene, but the production of 3-hydroxy-benzo(a)pyrene was not inhibited. Dietary BHA treatment also decreased the microsomal metabolism of trans-7,8-dihydroxy-7,8-dihydrobenzo(a)pyrene to n-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene and r-7,t-8-dihydroxy-c-9,10-oxy-7,8,9,10-tetrahydrobenzo(a)pyrene. Considering that the former diol-epoxide is a suspected ultimate carcinogen, the observed inhibitions of BP metabolism in the formation of diol-epoxides may be closely related to the anticarcinogenic action of BHA.