AP-1 and SP1 trans-activate the expression of hepatic CYP1A1 and CYP2A6 in the bioactivation of AFB1 in chicken

Dietary exposure to aflatoxin B 1 (AFB 1 ) is harmful to the health and performance of domestic animals. The hepatic cytochrome P450s (CYPs), CYP1A1 and CYP2A6, are the primary enzymes responsible for the bioactivation of AFB 1 to the highly toxic exo -AFB 1 -8,9-epoxide (AFBO) in chicks. However, the transcriptional regulation mechanism of these CYP genes in the liver of chicks in AFB 1 metabolism remains unknown. Dual-luciferase reporter assay, bioinformatics and site-directed mutation results indicated that specificity protein 1 (SP1) and activator protein-1 (AP-1) motifs were located in the core region −1,063/−948, −606/−541 of the CYP1A1 promoter as well as −636/−595, −503/−462, −147/−1 of the CYP2A6 promoter. Furthermore, overexpression and decoy oligodeoxynucleotide technologies demonstrated that SP1 and AP-1 were pivotal transcriptional activators regulating the promoter activity of CYP1A1 and CYP2A6 . Moreover, bioactivation of AFB 1 to AFBO could be increased by upregulation of CYP1A1 and CYP2A6 expression, which was trans -activated owing to the upregulalion of AP-1, rather than SP1, stimulated by AFB 1 -induced reactive oxygen species. Additionally, nano-selenium could reduce ROS, downregulate AP-1 expression and then decrease the expression of CYP1A1 and CYP2A6 , thus alleviating the toxicity of AFB 1 . In conclusion, AP-1 and SP1 played important roles in the transactivation of CYP1A1 and CYP2A6 expression and further bioactivated AFB 1 to AFBO in chicken liver, which could provide novel targets for the remediation of aflatoxicosis in chicks.