Aflatoxin B-1 metabolism: Regulation by phase I and II metabolizing enzymes and chemoprotective agents

Aflatoxin B-1 (AFB(1)) widely contaminates staple food and feed crops and is well-known as the most potent natural hepatocarcinogen in humans and domesticated animals. This review highlights significant advances in our understanding of the pivotal role of phase I and II metabolizing enzymes in the bioactivation and detoxification of AFB(1) and its metabolites across species. In humans, cytochrome P450 (CYP) 1A2, CYP3A4, CYP3A5, and CYP3A7 in liver and CYP2A13 in lung are essential for the bioactivation of AFB(1) to the extremely toxic exo-AFB(1)-8,9-epoxide (AFBO), whereas CYP1A1, CYP1A2, CYP2A6, and CYP3A4 are important in the turkey and duck, CYP1A1 and CYP2A6 are important in the chicken and quail, CYP3A11 and CYP3A13 are important in mice, and CYP2A5 are important in the hamster. In contrast, glutathione-S-transferase (GST) M1 and GSTT1 are primary responsible for detoxification of the AFB(1) by catalyzing the conjugation of GSH to AFBO in humans, whereas GSTM2 in a nonhuman primate, GSTA3 in mice, GSTA5 in rats, and GSTA1, GSTA2, GSTA3 and GSTA4 in the turkey are important. Additionally, microsomal epoxide hydrolase (mEH) and aflatoxin-aldehyde reductase (AFAR) have also been shown to play key roles in AFB(1) detoxification in the human, rat, and pig. Moreover, an overview of the chemoprotective agents, including synthetic compounds and naturally occurring plant compounds, which can be used to reduce aflatoxicosis is provided based on their ability to regulate these key enzymes. Collectively, this review summarizes the pivotal enzymes in the metabolism of AFB(1) among humans, experimental and farm animals, as well as the chemoprotective agents that can be used to minimize risk of aflatoxicosis.