2086

Aflatoxin B1 (AFB1), a mycotoxin produced by Aspergillus flavus and Aspergillus parasiticus, is a potent carcinogen in many animal models and in humans. Although AFB1 is best known to target the liver, there are epidemiological studies suggesting a link between human lung cancer and pulmonary exposure to AFB1-contaminated grain dusts. Previous studies have demonstrated that CYP1A2 and CYP3A4 are the principle enzymes in metabolic activation of AFB1 in human liver. In the present study, we determined the role of human CYP2A13, which is predominantly expressed in human respiratory tissues, in AFB1 metabolism. The heterologously expressed CYP2A13 displayed a significant activity in metabolizing AFB1 to its carcinogenic metabolites, AFB1-8,9-epoxide and AFM1-8,9-epoxide, as evidenced by the detection of AFB1-Diol and AFM1-Diol at both low (15 μM) and high (150 μM) substrate concentrations. At 15 μM AFB1 concentration, the activity of CYP2A13 is comparable to CYP1A2 in the formation of various AFB1 metabolites with the same efficiency in the formation of AFM1-Diol (Table 1). In addition, we discovered that Ala117 and His372 are important amino acid residues in CYP2A13 protein for its activity and stereo-selectivity in AFB1 metabolism (Table 1). Our results demonstrated that human CYP2A13 is efficient in AFB1 metabolic activation and suggest that CYP2A13 may play an important role in human lung cancer carcinogenesis related to inhalation exposure to AFB1 (Supported by the NIH Grant RO1-ES10048 to J-Y Hong and CA 90997 to J-S Wang).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]