Oxidation of carcinogenic 2-nitroanisole by rat cytochromes P450 - similarity between human and rat enzymes
2-Nitroanisole (2-NA) is an important industrial pollutant and a potent carcinogen for rodents. Understanding which cytochrome P450 (CYP) enzymes are involved in its metabolism are important to assess an individual's susceptibility to this environmental carcinogen. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 2-NA, to examine the metabolites formed during such an oxidation, and to compare such efficiencies of rat CYPs with those of human. 2-NA is oxidized by rat hepatic microsomes to 2-nitrophenol (2-NP) as the major metabolite, and to 2,6-dihydroxynitrobenzene (2,6-DNB) and 2,5-dihydroxynitrobenzene (2,5-DNB) as the minor products. All these metabolites are suggested as detoxication products. Using hepatic microsomes of rats pre-treated with specific CYP inducers and microsomes from Baculovirus transfected insect cells expressing recombinant rat and human CYP enzymes we found that rat recombinant CYP2E1, 2D2, 2B2, 2C6 and 1A1, as well as orthologous human CYP enzymes are the most efficient enzymes metabolizing 2-NA. However, human CYP1A1 oxidize 2-NA with a higher efficiency than the enzyme of rats. The results show the participation of orthologous CYPs in 2-NA oxidation by both species and underline the suitability of rat species as a model to evaluate human susceptibility to 2-NA.
Dračínská H, Mikšanová M, Svobodová M, Smrček S, Frei E, Schmeiser HH and Stiborová M (2006) Oxidative detoxication of carcinogenic 2-nitroanisole by human, rat and rabbit cytochrome P450. Neuro Endocrinol Lett27: 9-13.
Garner RC, Martin CN, Clayson DB (1984) (2nd ed. Searle C, Ed.) Carcinogenic aromatic amines and related compounds. Chemical Carcinogens, ACS Monograph 182, Vol. 1: pp. 175-302, American Chemical Society, Washington, DC.
IARC (1989) Diesel and gasoline engine exhausts and some nitroarenes. Monograph on the Evaluation of the carcinogenic risk to humans. Diesel Exhaust and Some Nitroarenes. Vol. 46, IARC, Lyon.
Mikšanová M, Novák P, Frei E and Stiborová M (2004a) Metabolism of carcinogenic 2-nitroanisole by rat, rabbit, porcine and human hepatic cytosol. Collect Czech Chem Commun69: 589-602.
Mikšanová M, Šulc M, Rýdlová H, Schmeiser HH, Frei E and Stiborová M (2004b) Enzymes involved in the metabolism of the carcinogen 2-nitroanisole: evidence for its oxidative detoxication by human cytochromes P450. Chem Res Toxicol17: 663-71.
NTP (1978) Bioassay of o-anisidine hydrochloride for possible carcinogenicity. NTP Technical Report 89, National Institute of Health, US Department of Health and Human Services, Bethesda, MD.
NTP (1993) Toxicology and Carcinogenesis. Studies of 2-nitroanisole. NTP Technical Report 416, National Institute of Health, US Department of Health and Human Services, Bethesda, MD.
Purohit V and Basu A (2000) Mutagenicity of nitroaromatic compounds. Chem Res Toxicol13: 673-692.
Stiborová M, Martínek V, Rýdlová H, Hodek P and Frei E (2002) Sudan I is a potential carcinogen for humans: evidence for its metabolic activation and detoxication by human recombinant cytochrome P450 1A1 and liver microsomes. Cancer Res62: 5678-5684.
Stiborová M, Martínek V, Schmeiser HH and Frei E (2006) Modulation of CYP1A1-mediated oxidation of carcinogenic azo dye Sudan I and its binding to DNA by cytochrome b5. Neuro Endocrinol Let27 (Suppl. 2): 35-39.
Stiborová M, Mikšanová M, Smrček S, Bieler CA, Breuer A, Klokow KA, Schmeiser HH, and Frei E (2004) Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans. Carcinogenesis25:833-40.
Stiborová M, Schmeiser HH and Frei E (1998) To the mechanism of 2-nitroanisole carcinogenicity: in vitro metabolism of 2-nitroanisole mediated by peroxidases and xanthine oxidase. Collect Czech Chem Commun63: 857-869.