Inhibition of trans-dihydrodiol oxidation by the non-steroidal anti-inflammatory drugs

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Abstract
The homogeneous dihydrodiol dehydrogenase of rat liver cytosol (EC 1.3.1.20) reduces the mutagenicity of benzo[a]pyrene in the Ames test, suggesting that the enzyme may detoxify the trans-dihydrodiol proximate carcinogens formed from this compound. This report directly demonstrates for the first time that the purified dehydrogenase catalyzes the NADP-dependent oxidation of the potent proximate carcinogen [1,3-3H](+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene at physiological pH. An initial velocity of 1.8 nmol [3H]trans-dihydrodiol oxidized/min/mg protein was observed at a substrate concentration of 20 microM. This potential detoxification reaction was potently inhibited by the nonsteroidal anti-inflammatory drug indomethacin, yielding an IC50 value of 10 microM. At higher drug concentrations (30 microM), the inhibition persisted for many hours. In an extension of this work, benzenedihydrodiol (trans-1,2-dihydroxy-3,5-cyclohexadiene) and naphthalenedihydrodiol (trans-1,2-dihydroxy-1,2-dihydronaphthalene) were synthesized as models of the scarce proximate carcinogen trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene and examined as substrates. The Km for benzenedihydrodiol was 1.74 mM and the Vmax was 530 nmol substrate oxidized/min/mg protein, while the Km for naphthalenedihydrodiol was 10.71 mM and the Vmax was 268 nmol oxidized/min/mg protein; the former compound was oxidized to catechol. Eight different non-steroidal anti-inflammatory drugs were found to inhibit the oxidation of these model trans-dihydrodiols, yielding IC50 values comparable to or lower than peak plasma concentrations observed in man. These results suggest that therapeutically relevant concentrations of the non-steroidal anti-inflammatory drugs may inhibit the oxidation of trans-dihydrodiol proximate carcinogens by this route.

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