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Key Role of Porcine Cytochrome P450 2A19 in the Bioactivation of Aflatoxin B1 in the Liver

文献类型： 外文期刊

作者： Wang, Zige 1 ; Huang, Qiang 1 ; Zhang, Feiyong 1 ; Wu, Jiajun 1 ; Wang, Lingling 1 ; Sun, Yu 1 ; Deng, Yiqun 1 ; Jiang, Jun 1 ;

作者机构： 1.South China Agr Univ, Coll Life Sci, Guangdong Prov Key Lab Prot Funct & Regulat Agr Or, Guangzhou 510642, Guangdong, Peoples R China

2.Guangdong Acad Agr Sci, Guangzhou 510640, Guangdong, Peoples R China

3.Guangdong Lab Lingnan Modern Agr, Guangzhou 510642, Guangdong, Peoples R China

4.South China Agr Univ, Key Lab Zoonosis, Minist Agr & Rural Affairs, Guangzhou 510642, Guangdong, Peoples R China

关键词： pig; CYP; AFB(1); hepatotoxicity

期刊名称：JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY （ 影响因子：6.1； 五年影响因子：6.3 ）

ISSN： 0021-8561

年卷期： 2024 年 72 卷 4 期

页码：

收录情况： SCI

摘要： The metabolic transformation of aflatoxin B1 (AFB1) in pigs remains understudied, presenting a gap in our toxicological understanding compared with extensive human-based research. Here, we found that the main products of AFB1 in porcine liver microsomes (PLMs) were AFB1-8,9-epoxide (AFBO), the generation of which correlated strongly with the protein levels and activities of cytochrome P450 (CYP)-3A and CYP2A. In addition, we found that porcine CYP2A19 can transform AFB1 into AFBO, and its metabolic activity was stronger than the other CYPs we have reported, including CYP1A2, CYP3A29, and CYP3A46. Furthermore, we stably transfected all identified CYPs in HepLi cells and found that CYP2A19 stable transfected HepLi cells showed more sensitivity in AFB1-induced DNA adducts, DNA damage, and gamma H2AX formation than the other three stable cell lines. Moreover, the CYP2A19 N297A mutant that lost catalytic activity toward AFB1 totally eliminated AFB1-induced AFB1-DNA adducts and gamma H2AX formations in CYP2A19 stable transfected HepLi cells. These results indicate that CYP2A19 mainly mediated AFB1-induced cytotoxicity through metabolizing AFB1 into a highly reactive AFBO, promoting DNA adduct formation and DNA damage, and lastly leading to cell death. This study advances the current understanding of AFB1 bioactivation in pigs and provides a promising target to reduce porcine aflatoxicosis.

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