INHIBITION OF MICROSOMAL METABOLISM AND CHEMICAL ONCOGENESIS IN CULTURE BY NAPHTHALENE QUINONES

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 4  (5-6) , 17-30
Abstract
Naphthalene diols, quinones and related compounds were examined for their ability to inhibit mixed-function oxidase activities in liver microsomes obtained from rats pretreated with 3-methylcholanthrene (3-MC) or phenobarbital (PB). Using benzo(a)pyrene [BAP] 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 .mu.M. Phenanthrene-9,10-quinone did not affect cytochrome c reductase but did inhibit aminopyrine N-demethylase and p-nitroanisole-O-demethylase in 3-MC and PB-induced microsomes 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 BAP monooxygenase with phenanthrene-9,10-quinone and 1,2-naphthoquinone indicated that they were noncompetitive with BAP and mixed noncompetitive with NADPH. Both quinones inhibited BAP induced oncogenic transformation in C3H10T1/2CL8 [mouse] cells in culture in a dose response manner, presumably by inhibition of the cellular microsomal enzymes which activate BAP. 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.