Effects of Inducers and Epoxide Hydrase on the Metabolism of Benzo[ a ]pyrene by Liver Microsomes and a Reconstituted System: Analysis by High Pressure Liquid Chromatography

Abstract

The mobilities of 24 potential metabolites of benzo [a] The widespread occurrence of benzo[a]pyrene (BP) as an environmental contaminant (1) and the carcinogenic effects of BP in experimental animals (2) have stimulated interest in this compound for some 40 years. This interest is manifested by numerous metabolic studies of BP both in vivo (3-9) and in vitro (10-17), the testing of BP and its metabolites for their carcinogenic and mutagenic potency (18,19), and binding studies of BP and its metabolites to nucleic acids and polynucleotides (15,(20)(21)(22)(23). The growing evidence that arene oxides are ultimate carcinogens of polycyclic aromatic hydrocarbons (24,25), and the established intermediacy of arene oxides in the metabolism of several of these hydrocarbons (26)(27)(28)(29), make a critical examination of the metabolism of BP imperative. Recent studies of BP metabolism in vitro have Abbreviations used: BP, benzo[a]pyrene; 1-HOBP, 1-hydroxybenzo[a]pyrene; 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, and 12-HOBP, other BP phenols; BP 1,6-quinone, benzo[a]pyrene 1,6-quinone; BP 3,6-quinone, BP 4,5-quinone, BP 6,12-quinone, and BP 11,12-quinone, other BP quinones; BP 1,2-dihydrodiol, trans-1,2-dihydroxy-1,2-dihydrobenzo [alpyrene; BP 2,4,7,9,[10][11] other

Tumorigenicity of the optical enantiomers of the diastereomeric benzo[a]pyrene 7,8-diol-9,10-epoxides in newborn mice: exceptional activity of (+)-7beta,8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene.

“…The environmental carcinogen benzo [a]pyrene (BP) is metabolized by microsomal enzymes to arene oxides, phenols, quinones, dihydrodiols, and diol epoxides (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The BP-7,8-diol-9,10-epoxides derived from BP-7,8-dihydrodiol exist as a pair of diastereomers in which the 7-hydroxyl group is either cis (diol epoxide 1) or trans (diol epoxide 2) to the 9,10-epoxide.…”

Purification and characterization of the hepatic microsomal monooxygenase system from the coastal marine fish Stenotomus chrysops

“…Yet, a simi lar pattern of prominent quinones has been observed wi th reconsti tutions of the major aromatic hydrocarbon-inducible cytochrome P-4SØ purified from rat (Holder et al, 1974) and adult rabbit livers (LM-4; in the absence of epoxide hydrolase. Benzo-ring dihydrodiols increased roughly ten-fold to 36% of the total hydroxylated products when epoxide hydrolase was added to the rat cytochrome P-4SØ reconstitution (Holder et al, 1974). (Stegeman and Woodin,19SØ).…”

Xenobiotic monooxygenase activity and the response to inducers of cytochrome P-450 during embryonic and larval development in fish

“…Since cytochrome b5 can be reduced by elec trons from NADPH and can transfer electrons to cytochrome P-450, it apparently can also playa role in NADPH-dependent cytochrome P-450 mediated reactions (Estabrook, 1971;Lu and Levin, 1974b). The involvement of cytochrome b5 in the NADPH-dependent pathway seems to depend on the type of substrate and the particular species of cytochrome P-450 catalyzing the reaction; for many substrates, cytoch rome b5 is not an obligatory component of this pathway (Jansson and Schenkman, 1973;Lu and Levin, 1974b;Lu et al, 1974;Sugiyama et 21., 1979).…”

“…The mammalian liver cytochrome P-450 isozymes induced by PB and 3-MC show different positional and stereospecificity in metabolizing BP (Holder et ~., 1974;Pezzuto ~ al., 1978;Rasmussen and Wang, 1974;Yang et ~., 1975;Yang et ~., 1978). The major isozymes induced by 3-MC in rats and rabbits produce more benzo-ring metabolites than the isozymes induced by PB.…”