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Kinetics and cofactor requirements for the nitroreductive metabolism of 1-nitropyrene and 3-nitrofluoranthene by rabbit liver aldehyde oxidase
Department of Environmental Health Sciences, School of Medicine, Case Western Reserve University Cleveland, OH 44106–4940, USA
Nitrated polycyclic aromatic hydrocarbons are environmental pollutants that have been shown to arise from a variety of sources, including diesel exhaust emissions and urban air. Most of these compounds are mutagenic in in vitro tests, and several have been shown to be carcinogenic in animals. We have investigated the kinetics of the metabolism of two of these compounds, 1-nitropyrene and 3-nitrofluoranthene, using rabbit liver aldehyde oxidase, an emyme that has been shown to catalyze the bioactivation of 1-nitropyrene. The nitroreduction of 20 µM [4,5,9,10-3-H]1-nitropyrene or 20 µM [4-3H]3-nitrofluoranthene by aldehyde oxidase required the presence of flavin mononucleotide (FMN) or flavin adenine dinucleotide (FAD), and was inhibited by oxygen in a concentration-dependent manner. In contrast, the aldehyde oxidase oxidation of the electron donor 1-methylnicotinamide did not require FMN or FAD, indicating that the aldehyde oxidase was not isolated as an apoenzyme. The aldehyde oxidase Km and Vmax, for 1-nitropyrene were 4.2 µM and 16.3 pmol/min/unit enzyme, while the respective values for 3-nitrofluoranthene nitroreduction were 1.9 µM and 5.4 pmol/min/unit enzyme. The requirement for flavins in the nitroreduction of 1-nitropyrene and 3-nitrofluoranthene suggests that reduced free flavins may be required in cytosolic nitroreduction of 1-nitropyrene and 3-nitrofluoranthene. More importantly, the inhibition of nitroreduction by concentrations of oxygen that are representative of intracellular concentrations strongly suggests that the reasons for the apparent lack of 1-nitropyrene nitroreduction in vivo may be due to oxygen-mediated oxidation of a reduced metabolite of 1-nitropyrene.
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