The critical role of porcine cytochrome P450 3A46 in the bioactivation of aflatoxin B1

Biochemical Pharmacology
Haoran JiangYiqun Deng

Abstract

Aflatoxin B1 (AFB1) is bioactivated by cytochrome P450 (CYP) 3A isoforms in humans to generate the highly reactive epoxide intermediate AFB1-8,9-epoxide (AFBO), causing hepatotoxicity and hepatocarcinoma. Due to the unavoidable contamination in their feed, pigs are more likely to be exposed to AFB1 and indirectly harm human health. Therefore, identifying the porcine CYP3A isoforms involved in AFB1-8,9-epoxidation is critical. In this study, we used codon optimization and N-terminal coding sequence modification to modify a CYP3A46 recombinant protein that exhibits good structure and catalytic activities and revealed its strong AFB1-8,9-epoxidase activity for the first time. Site-directed mutagenesis, kinetics and docking analyses were performed and demonstrated that residues Phe-108, Ser-119, Phe-215, Phe-304 and Thr-309 play important roles in AFB1-8,9-epoxidation and its responsiveness to α-naphthoflavone. Interestingly, we uncovered the dual and reverse roles of Phe-304 in CYP3A46, CYP3A5 and CYP3A4 in AFB1 oxidation. Unlike the π-π interaction between the Phe-304 phenyl of CYP3A4 and the AFB1 aromatic ring, Phe-304 of CYP3A46 may function to provide steric hindrance to bind AFB1. Phe-108 and Phe-215 could stabilize AFB1 with...Continue Reading

Citations

Jan 31, 2020·Oxidative Medicine and Cellular Longevity·Abdullah M Alzahrani, Peramaiyan Rajendran
Dec 25, 2019·Scientific Reports·Mery GiantinMauro Dacasto
Mar 17, 2020·Archives of Toxicology·Martin Krøyer Rasmussen
Aug 11, 2021·Signal Transduction and Targeted Therapy·Qing ZhuYuchen Jiao

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