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

Using brain, lung and liver microsomes as the enzyme sourcein in vitro assays, benzo[a]pyrene (B[a]P) metabolism was studiedin fetuses and dams of mice (C57B1/6) and rats (WAG). Separationand quantitation of B[a]P metabolites were performed by h.p.l.c.Microsomal preparations were tested for cytochrome P-450 dependentO-dealkylatlon of 7-ethoxycoumarin and epoxide hydrolase activities.Another parameter measured included the conjugation of 1-chloro-2,4dinitrobenzene to glutathione by cytosolic glutathione-S-transferaseactivity. The induction of B[a]P metabolism was studied aftertreatment of animals with 5,6-benzoflavone (BF). Mixed functionoxygenase, epoxide hydrolase and glutathione-S-transferase activiteswere transpiacentally inducible after dams were treated withBF. Metabolic activation of B[a]P by fetal brain microsomeswas lower in both species than that by fetal lung and livermicrosomes, but it was higher in fetuses than in adults. Allmetabolites of B[a]P increased after BF treatment; the productionof 7,8-dihydro-7,8-dihydroxybenzo[a]pyrene (7,8-dihydrodiolB[a]P) was higher in brain microsomes from BF-treated rats thanthat in mice. In stimulated rats, the formation of 7,8-dihydrodiolB[a]P by fetal brain microsomes was higher than that by fetallung microsomes, whereas in mice, the opposite was observed.These data suggest that initiation could occur in utero, andpartially explain the species-specific differences in susceptibilityto transplacental tumorigenesis by polycyclic aromatic hydrocarbonsby differences in biotransformation in the target organ.