Substrate selectivity of human aldehyde oxidase 1 in reduction of nitroaromatic drugs

Human aldehyde oxidase 1 (AOX1) catalyzes the oxidation of various drugs and endogenous compounds. Recently, we found that AOX1 catalyzed the reduction of drugs such as nitrazepam and dantrolene. In this study, we aimed to clarify the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs to obtain helpful information for drug development. We investigated whether 11 nitroaromatic drugs were reduced by AOX1 using recombinant AOX1 and human liver cytosol (HLC) in the presence of N¹-methylnicotinamide, an electron donor to AOX1. We found that clonazepam, flunitrazepam, flutamide, nilutamide, nimesulide, and nimetazepam were substantially reduced by recombinant AOX1 and HLC, whereas azelnidipine, nifedipine, and nimodipine were slightly reduced and metronidazole and tolcapone were not reduced. Via structural analysis, we observed that nitroaromatic drugs reduced by AOX1 possessed a relatively electron-deficient nitro group. Since the addition of NADPH to human liver microsomes (HLM) did not increase the reductase activities of the drugs that were reduced by recombinant AOX1, it was determined that NADPH-dependent enzymes in microsomes, such as cytochrome P450, were not involved in this process. Inhibition studies using known AOX1 inhibitors supported the role of AOX1 in the reduction of drugs in HLC. In conclusion, this provides new information related to the substrate selectivity of human AOX1 for the reduction of nitroaromatic drugs.