Inhibition of benzo(alpha)pyrene metabolism catalyzed by mouse and hamster lung microsomes.
Induced and constitutive microsomal enzymes of mouse and hamster lungs catalyze both the hydroxylation of benzo(alpha)pyrene and reactions that lead to its irreversible binding to macromolecules. For mouse and hamster, the induced lung hydroxylases have Km values of 1.10 and 0.52 muM, respectively. The induced hydroxylases are strongly inhibited by 7,8-benzoflavone and are stimulated by cyclohexene oxide, an inhibitor of epoxide hydrase. Formation of the macromolecular product by the induced "binding" enzyme follows. Michaelis-Menten kinetics, except for substrate inhibition, and has Km values of 0.52 and 0.25 muM for lung microsomes from mouse and hamster, respectively. These reactions are also inhibited by 7,8-benzoflavone. The reaction catalyzed by the constitutive hydroxylase of mouse lungs is characterized by a brief lag period but proceeds in a linear fashion after the lag. The enzyme requires 60 muM benzo(alpha)pyrene to achieve maximum reaction velocity. Above this concentration, strong substrate inhibition is observed; accurate values for Vmax and Km cannot be derived. The constitutive hydroxylases are moderately inhibited by butylated hydroxytoluene, retinol, cyclohexene oxide, and 7,8-benzoflavone. The product of the constitutive "binding" enzyme is formed in a reaction that follows Michaelis-Menten kinetics. The Km value for enzymes from mouse and hamster lungs are 11.8 and 4.9 muM, respectively. Formation of this product is strongly inhibited by butylated hydroxytoluene and by retinol but not strongly by 7,8-benzoflavone or cyclohexene oxide. Since other evidence indicates that a constitutive enzyme may be involved in carcinogenesis by benzo(alpha)pyrene and since this reaction is inhibited by two known anticarcinogens, we suggest that it may be involved in this process.
D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000037:antagonists & inhibitors*; D001580:Benzopyrenes / Q000378:metabolism*; D002084:Butylated Hydroxytoluene / Q000494:pharmacology; D006224:Cricetinae; D003510:Cyclohexanes / Q000494:pharmacology; D004790:Enzyme Induction; D005419:Flavonoids / Q000494:pharmacology; D007700:Kinetics; D008168:Lung / Q000201:enzymology*; D051379:Mice; D008861:Microsomes / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010087:Oxides; D014801:Vitamin A / Q000494:pharmacology
D001580:Benzopyrenes; D003510:Cyclohexanes; D005419:Flavonoids; D010087:Oxides; D014801:Vitamin A; D002084:Butylated Hydroxytoluene; D006899:Mixed Function Oxygenases; D001579:Benzopyrene Hydroxylase