Inhibition of microsomal metabolism and chemical oncogenesis in culture by naphthalene quinones.
A series of naphthalene diols, quinones, and related compounds were examined for their ability to inhibit mixed-function oxidase in liver microsomes obtained from rats which had been pretreated with 3-methylcholanthrene (3-Mc) or phenobarbital (PB). Using benzo(a)pyrene monooxygenase as a measure of mixed-function oxidase activity, it was found that phenanthrene-9, 10-quinone was the most active compound tested with a K1 = 0.79 microM. Phenanthrene-9, 10-quinone did not affect cytochrome c reductase but did inhibit aminopyrine N-demethylase and p-nitroanisole-O-demethylase in both 3-MC and PB-induced microsome with almost identical inhibition constants. 1,2-Naphthoquinone exerted similar effects as phenanthrene-9,10-quinone on cytochrome c reductase, aminopyrine N-demethylase and p-nitroanisole-O-demethylase. Both quinones stimulated NADPH oxidase activity but the extent of this stimulation did not explain their inhibition of microsomal oxidation. Kinetic studies using benzo(a)-pyrene monooxygenase with phenanthrene-9, 10-quinone and 1,2-naphthoquinone indicated that they were noncompetitive with benzo(a)pyrene and mixed noncompetitive with NADPH. Both of these quinones inhibited benzo(a)pyrene induced oncogenic transformation in C3H10T1/2CL8 cells in culture in a dose response manner, presumably by inhibition of the cellular microsomal enzyme which activate benzo(a)pyrene. Phenanthrene-9, 10-quinone and 1,2-naphthoquinone seem to inhibit microsomal oxidative processes by interaction at the level of cytochrome P-450 possibly with a cytochrome P-450-substrate-oxygen complex.
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001579:Benzopyrene Hydroxylase / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D003470:Culture Media; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D009281:Naphthalenes / Q000633:toxicity*; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D011809:Quinones / Q000633:toxicity*; D051381:Rats
D003470:Culture Media; D009281:Naphthalenes; D011809:Quinones; D009575:Nitroanisole O-Demethylase; D001579:Benzopyrene Hydroxylase; D000633:Aminopyrine N-Demethylase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D009245:NADH Dehydrogenase