Involvement of Molybdenum Hydroxylases in Reductive Metabolism of Nitro Polycyclic Aromatic Hydrocarbons in Mammalian Skin

Abstract

ABSTRACT: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, N 1 -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.

Low levels of the air pollutant 1-nitropyrene induce DNA damage, increased levels of reactive oxygen species and endoplasmic reticulum stress in human endothelial cells

“…Nitroreductases have been suggested to play a role in the metabolic activation of 1-NP in cultured human liver cells (Silvers et al, 1997;Sun et al, 2004). Both xanthine oxidase and NAD(P)H:quinone oxidoreductase 1 have been associated with nitroreduction of 1-NP and are expressed in the vascular wall (Saito et al, 1984;Siegel and Ross, 2000;Ueda et al, 2005;Zhu et al, 2007). We employed dicoumarol, an inhibitor of xanthine oxidase and NAD(P)H:quinone oxidoreductase 1, to reduce the nitroreductive metabolism in HUVEC (Gustafson and Pritsos, 1992).…”

Nicotinamide overload may play a role in the developmentof type 2 diabetes

“…Of the factors, skin may be of particular significance because it takes part in N 1 -methylnicotinamide detoxification and excretion, respectively, through skin AOX [26,27] and sweat glands [28] . We thus explored the role of skin by analyzing human sweat excretion of nicotinamide and N 1 -methylnicotinamide after nicotinamide loading, or by assessing changes in plasma N 1 -methylnicotinamide clearance of rats with severe skin damage.…”

VX-509 (Decernotinib)-Mediated CYP3A Time-Dependent Inhibition: An Aldehyde Oxidase Metabolite as a Perpetrator of Drug-Drug Interactions

“…AO belongs to a family of enzymes referred to as molybdenum cofactor-containing enzymes that also include xanthine oxidase . AO is predominantly expressed in the liver, lung, and kidney, and is present in the intestine (Moriwaki et al, 2001;Ueda et al, 2005;Sahi et al, 2008). It is involved in the phase I metabolism of xenobiotics, including anti-infectives, anticancer compounds, antiepileptics, and antipsychotics (Rashidi et al, 1997;Al-Salmy, 2001;Beedham et al, 2003;Obach, 2004;Obach et al, dx.doi.org/10.1124/dmd.116.071100. s This article has supplemental material available at dmd.aspetjournals.org.…”