Vitamin A compounds and analogs as inhibitors of mixed-function oxidases that metabolize carcinogenic polycyclic hydrocarbons and other compounds.

Fourteen vitamin A compounds and analogs have been evaluated as inhibitors of microsomal mixed-function oxi dases from liver and lung tissues of mice and hamsters. With liver microsomes, benzo(a)pyrene (BP) is metabolized, by one pathway, to a product (BP-X) which is tightly bound to reaction components. The Km for BP in this reaction is 10 ± 2 /xM.The formation of BP-X is strongly inhibited by retinol and several other vitamin A compounds, some of which have known anticartinogenic activity, and by butylated hydroxytoluene, also an anticarcinogenic agent. BP-X accu mulates in larger amounts in the presence of cyclohexene oxide, an inhibitor of epoxide hydrase. 7,12-Dimethylbenzanthracene and 3-methylcholanthrene are also converted by liver microsomal oxidases to tightly bound metabolites, the formation of which is inhibited by the compounds that block production of BP-X. BP is converted to 3-hydroxy-BP in another metabolic step, a reaction not inhibited by any of the vitamin A compounds. The Km for BP in this reaction is 8.5 JUM. 3-Hydroxy-BP is further metabolized by a microsomal oxidase to a product (BP-Y), which, by mass spectral analysis, contains 2 oxygen atoms. The Km for 3-hydroxyBP is 3 /¿M. The disappearance of this substrate is inhibited by retinol and some of its derivatives and by butylated hydroxytoluene. Enzymes that catalyze the oxidation of cyclophosphamide and nicotine to hydroxy derivatives are also inhibited by the agents that block production of BP-X and metabolism of 3-hydroxy-BP, but amine oxidases that use nicotine and trimethylamine as substrates are not inhibited. Microsomes from the lungs of mice pretreated with benz(n)anthracene convert BP to 3-hydroxy-BP but show no detectable formation of BP-X or further metabolism of 3-hydroxy-BP.