Metabolism of benzo[a]pyrene by brain microsomes of fetal and adult rats and mice. Induction by 5,6 benzoflavone, comparison with liver and lung microsomal activities

Abstract

Using brain, lung and liver microsomes as the enzyme source in in vitro assays, benzo[a]pyrene (B[a]P) metabolism was studied in fetuses and dams of mice (C57B1/6) and rats (WAG). Separation and quantitation of B[a]P metabolites were performed by h.p.l.c. Microsomal preparations were tested for cytochrome P-450 dependent O-dealkylatlon of 7-ethoxycoumarin and epoxide hydrolase activities. Another parameter measured included the conjugation of 1-chloro-2,4 dinitrobenzene to glutathione by cytosolic glutathione-S-transferase activity. The induction of B[a]P metabolism was studied after treatment of animals with 5,6-benzoflavone (BF). Mixed function oxygenase, epoxide hydrolase and glutathione-S-transferase activites were transpiacentally inducible after dams were treated with BF. Metabolic activation of B[a]P by fetal brain microsomes was lower in both species than that by fetal lung and liver microsomes, but it was higher in fetuses than in adults. All metabolites of B[a]P increased after BF treatment; the production of 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (7,8-dihydrodiol B[a]P) was higher in brain microsomes from BF-treated rats than that in mice. In stimulated rats, the formation of 7,8-dihydrodiol B[a]P by fetal brain microsomes was higher than that by fetal lung microsomes, whereas in mice, the opposite was observed. These data suggest that initiation could occur in utero, and partially explain the species-specific differences in susceptibility to transplacental tumorigenesis by polycyclic aromatic hydrocarbons by differences in biotransformation in the target organ.