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

✍ Scribed by Xiao-Yang He; Lili Tang; Shou-Lin Wang; Qing-Song Cai; Jia-Sheng Wang; Jun-Yan Hong

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: French
• Weight: 338 KB
• Volume: 118
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.21665

✦ Synopsis

Abstract

The worldwide human exposure to aflatoxin B~1~ (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 μM) and high (150 μM) 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 ∼800‐fold difference in LC~50~ values of AFB~1~ (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 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.~ © 2005 Wiley‐Liss, Inc.