Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract

The worldwide human exposure to aflatoxin B, (AFB(1)), particularly in developing countries, remains to be a serious public health concern. Although AFB(1) is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB(1). Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB(1) to exert its carcinogenicity. Previous studies have identified CYP1A2 and CYP3A4 as the major enzymes for AFB(1) activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB(1) in situ are unknown. In the present study, we demonstrate that CYP2A13, an enzyme predominantly expressed in human respiratory tract, has a significant activity in metabolizing AFB(1) to its carcinogenic/toxic AFB(1)-8,9-epoxide and AFM(1)-8,9-epoxide at both low (15 mu M) and high (150 mu M) substrate concentrations. Under the same conditions, there was no detectable AFB(1) epoxide formation by CYP2A6, which was also reported to be involved in the metabolic activation of AFB(1). Consistent with the activity data, there was an similar to 800-fold difference in LC50 values of AFB(1) (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 mu M). We further demonstrate that amino acid residues Ala(117) and His(372) in CYP2A13 protein are important for AFB(1) epoxidation and its related cytotoxicity. Our results suggest that CYP2A13-catalyzed metabolic activation in situ may play a critical role in human lung carcinogenesis related to inhalation exposure to AFB(1). (c) 2005 Wiley-Liss, Inc.