The first three authors contributed equally to this work.
Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract†
Article first published online: 29 DEC 2005
Copyright © 2005 Wiley-Liss, Inc.
International Journal of Cancer
Volume 118, Issue 11, pages 2665–2671, 1 June 2006
How to Cite
He, X.-Y., Tang, L., Wang, S.-L., Cai, Q.-S., Wang, J.-S. and Hong, J.-Y. (2006), Efficient activation of aflatoxin B1 by cytochrome P450 2A13, an enzyme predominantly expressed in human respiratory tract. Int. J. Cancer, 118: 2665–2671. doi: 10.1002/ijc.21665
Part of this work was presented at the 96th Annual Meeting of American Association for Cancer Research (April 2005).
- Issue published online: 14 MAR 2006
- Article first published online: 29 DEC 2005
- Manuscript Accepted: 7 OCT 2005
- Manuscript Received: 10 AUG 2005
- The NIH. Grant Numbers: ES10048, ES05022, CA90997
- cytochrome P450 2A13;
- aflatoxin B1;
- metabolic activation;
The worldwide human exposure to aflatoxin B1 (AFB1), particularly in developing countries, remains to be a serious public health concern. Although AFB1 is best known as a hepatocarcinogen, epidemiological studies have shown a positive association between human lung cancer occurrence and inhalation exposure to AFB1. Cytochrome P450 (CYP)-catalyzed metabolic activation is required for AFB1 to exert its carcinogenicity. Previous studies have identified CYP1A2 and CYP3A4 as the major enzymes for AFB1 activation in human liver. However, the key CYP enzymes in human lung that can efficiently activate AFB1in 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 AFB1 to its carcinogenic/toxic AFB1-8,9-epoxide and AFM1-8,9-epoxide at both low (15 μM) and high (150 μM) substrate concentrations. Under the same conditions, there was no detectable AFB1 epoxide formation by CYP2A6, which was also reported to be involved in the metabolic activation of AFB1. Consistent with the activity data, there was an ∼800-fold difference in LC50 values of AFB1 (48-hr treatment) between Chinese hamster ovary (CHO) cells expressing CYP2A13 and CYP2A6 (50 nM versus 39 μM). We further demonstrate that amino acid residues Ala117 and His372 in CYP2A13 protein are important for AFB1 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 AFB1. © 2005 Wiley-Liss, Inc.