Polycyclic aromatic hydrocarbon trans-dihydrodiol specificity of four recombinant human dihydrodiol dehydrogenase isoforms

A major metabolic route of polycyclic aromatic hydrocarbon (PAH) activation proceeds through trans-dihydrodiol intermediates. We have previously shown that a member of the aldo-keto reductase (AKR) superfamily, rat liver dihy drodiol dehydrogenase (DD), catalyzes the NAD(P)(+)-dependent oxidation of PAH trans-dihydrodiols with the concomitant production of reactive oxygen s pecies and o-semiquinone anion radicals on route to cyto- and gene-toxic o- quinones. The relevance of this pathway in humans, however, is unknown. In these studies, four homogeneous recombinant human homologs of rat liver DD (DD1, DD2, DD4 and DDX) were tested for their ability to oxidize a structur al series of PAH trans-dihydrodiols of increasing ring size and methylation . The results indicate that human DDs preferred non-K-region trans-dihydrod iols and that methyl substitution enhanced oxidation rates by human DDs. Th us multiple human AKRs can contribute to the activation of structurally div erse procarcinogenic PAH by catalyzing the NAD(P)(+)-dependent oxidation of PAH trans-dihydrodiols to detrimental o-quinones.