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Drug Metabolism and Disposition Fast Forward
First published on June 2, 2005; DOI: 10.1124/dmd.105.005306

0090-9556/05/3309-1312-1318$20.00
DMD 33:1312-1318, 2005

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*POLYCYCLIC AROMATIC HYDROCARBONS

INVOLVEMENT OF MOLYBDENUM HYDROXYLASES IN REDUCTIVE METABOLISM OF NITRO POLYCYCLIC AROMATIC HYDROCARBONS IN MAMMALIAN SKIN

Osamu Ueda, Kazumi Sugihara, Shigeru Ohta, and Shigeyuki Kitamura

Hiroshima University, Graduate School of Biomedical Sciences, Hiroshima, Japan

Molybdenum hydroxylases, aldehyde oxidase and xanthine oxidoreductase, were shown to be involved in the nitroreduction of 2-nitrofluorene (NF), 1-nitropyrene, and 4-nitrobiphenyl, environmental pollutants, in the skin of various mammalian species. NF was reduced to 2-aminofluorene by hamster skin cytosol in the presence of 2-hydroxypyrimidine, 4-hydroxypyrimidine, N1-methylnicotinamide, or benzaldehyde, but not hypoxanthine or xanthine. Inhibitors of aldehyde oxidase markedly inhibited these nitroreductase activities, but oxypurinol, an inhibitor of xanthine oxidoreductase, had little effect. In DEAE column chromatography of hamster skin cytosol, the major fraction exhibiting nitroreductase activity also showed aldehyde oxidase activity. 2-Hydroxypyrimidine-linked nitroreductase activities of skin cytosol from rabbits and guinea pigs were also inhibited by an inhibitor of aldehyde oxidase. In contrast, nitroreductase activities of skin cytosols of rats and mice were markedly inhibited by oxypurinol. When aldehyde oxidase activity was estimated in skin cytosol of various mammals using benzaldehyde oxidase activity as a marker, considerable variability of the activity was found. The highest activity was observed with hamsters, and the lowest activity with rats. On the other hand, the highest xanthine oxidoreductase activity was observed with rats, and the lowest activity with rabbits. These skin cytosols of various mammals also exhibited significant 2-hydroxypyrimidine-linked nitroreductase activities toward 1-nitropyrene and 4-nitrobiphenyl catalyzed by aldehyde oxidase and xanthine oxidoreductase. Thus, NF was mainly reduced by aldehyde oxidase and xanthine oxidoreductase in skins of animals. However, the contributions of these two molybdenum hydroxylases were considerably different among animal species.

Address correspondence to: Dr. Shigeyuki Kitamura, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan. E-mail: skitamu{at}hiroshima-u.ac.jp






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