Abstract
The metabolism and activation of the pulmonary carcinogen, benzo(a)pyrene, have been examined in reconstituted rabbit pulmonary monooxygenase systems. Two forms of purified pulmonary cytochrome P-450, which are known to have different monomeric molecular weights, spectral properties, and substrate specificities, were compared. Metabolite profiles were obtained using high pressure liquid chromatography. Metabolites that chromatographed with the 3-hydroxy and quinone standards accounted for 95% of the total activity of cytochrome I. With cytochrome II metabolism at positions 9 and 10 accounted for 40 to 50% of the total activity; products that chromatographed with the 3-hydroxy standard were 30 to 40% of the total. Formation of the 4,5- or 7,8-dihydrodiol metabolites accounted for less than 5% of the total produced by either cytochrome. The metabolism of benzo(a)pyrene by cytochrome II was inhibited by ..cap alpha..-naphthoflavone (K/sub i/ = 8.2 +- 0.4 x 10/sup -9/ M) in a manner that did not affect the profile of the metabolites produced. Metabolism by cytochrome I was not significantly inhibited by ..cap alpha..-naphthoflavone at a concentration of 10/sup -4/ M. Cytochrome II, unlike cytochrome I, catalyzed the metabolism of benzo(a)pyrene to products that bound covalently to DNA. The involvement of the two pulmonary cytochromes in the formationmore » of potentially carcinogenic metabolites from benzo(a)pyrene is discussed.« less
Highlights
National Institute of Environmental Health Sciences, Research Triangle Park, The metabolism and activation of the pulmonary carcinogen, benzo(a)pyrene, have been examined in reconstituted rabbit pulmonary monooxygenase systems
We have investigated the metabolism of benzo(a)pyrene in purified, reconstituted rabbit pulmonary monooxygenase systems with particular emphasis on the metabolic profiles, factors affecting the profiles, and the binding of metabolites to DNA
No activity was detected with either cytochrome when NADPH or NADPH-cytochrome P-450 reductase was omitted from the incubations (Table I)
Summary
National Institute of Environmental Health Sciences, Research Triangle Park, The metabolism and activation of the pulmonary carcinogen, benzo(a)pyrene, have been examined in reconstituted rabbit pulmonary monooxygenase systems. Metabolites that cbromatographed with the 3-hydroxy and quinone standards accounted for 95% of the total activity of cytochrome I. With cytochrome II metabolism at positions 9 and 10 accounted for 40 to 50% of the total activity; products that chromatographed with the 3-hydroxy standard were 30 to 40% of the total. Formation of the 4,6- or 7,tLdihydrodiol metabolites accounted for less than 5% of the total produced by either cytochrome. The metabolism of benzo(a)pyrene by cytochrome II was inhibited by a-naphthoflavone (Ki = 8.2 f 0.4 x lo-’ m) in a manner that did not affect the profile of the metabolites produced. Metabolism by cytochrome I was not significantly inhibited by a-naphthoflavone at a concentration of 10m4 M.
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