Collect. Czech. Chem. Commun. 2004, 69, 589-602

Metabolism of Carcinogenic 2-Nitroanisole in Rat, Rabbit, Porcine and Human Hepatic Cytosol

Markéta Mikšanováa, Petr Novákb, Eva Freic and Marie Stiborováa,*

a Department of Biochemistry, Charles University in Prague, Albertov 2030, 128 40 Prague 2, Czech Republic
b Institute of Microbiology, Academy of Sciences of the Czech Republic, 142 20 Prague 4, Czech Republic
c Department of Molecular Toxicology, German Cancer Research Center, 69120 Heidelberg, Germany


We investigated the ability of hepatic cytosolic samples from human, rat, rabbit and pig to metabolize an important industrial pollutant and a potent carcinogen for rodents, 2-nitroanisole (1-methoxy-2-nitrobenzene). A comparison between experimental animals and the human enzymatic system is essential for the extrapolation of animal carcinogenicity data to humans to assess a health risk to humans. Two major metabolites produced from 2-nitroanisole by cytosols of all species were N-(2-methoxyphenyl)hydroxylamine and 2-methoxyaniline. An additional minor product of 2-nitroanisole metabolism has not yet been characterized. Both the identified metabolites are generated from 2-nitroanisole by reduction of the nitro group. To define the role of cytosolic reductases in the reduction of 2-nitroanisole, we investigated the modulation of 2-nitroanisole reduction by cofactors of the cytosolic reductases, DT-diaphorase and xanthine oxidase. The role of the human enzymes in 2-nitroanisole reduction was also investigated by correlating the xanthine oxidase-linked catalytic activities in each human cytosolic sample with the concentration of the 2-nitroanisole reduction product, 2-methoxyaniline, formed by the action of the same cytosol. On the basis of these analyses, most of hepatic cytosolic reduction of 2-nitroanisole was attributed to xanthine oxidase, but participation of DT-diaphorase in the reduction of this carcinogen in hepatic cytosols of rabbit and pigs cannot be excluded. Using the purified xanthine oxidase, its participation in 2-nitroanisole reduction was confirmed. The data clearly demonstrate the predominant role of xanthine oxidase in 2-nitroanisole reduction in human and rat hepatic cytosols and suggest a carcinogenic potency of this rodent carcinogen for humans.

Keywords: Nitro compounds; Environmental pollutants; Carcinogens; Risk assessment; Metabolism; Cytosolic reductases; Xanthine oxidase; DT-Diaphorase; Enzymatic reductions.

References: 37 live references.