Dietary exposure to aflatoxin B1 (AFB1) 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 AFB1 to the highly toxic exo-AFB1-8,9-epoxide (AFBO) in chicks. However, the transcriptional regulation mechanism of these CYP genes in the liver of chicks in AFB1 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 AFB1 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 AFB1-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 AFB1. In conclusion, AP-1 and SP1 played important roles in the transactivation of CYP1A1 and CYP2A6 expression and further bioactivated AFB1 to AFBO in chicken liver, which could provide novel targets for the remediation of aflatoxicosis in chicks.

• Klíčová slova
• AP-1, CYP1A1, CYP2A6, SP1, aflatoxin B1, transcriptional activation,
• MeSH
• aflatoxin B1 * metabolismus   MeSH
• aktivace transkripce MeSH
• cytochrom P-450 CYP1A1 * genetika   metabolismus   MeSH
• cytochrom P450 CYP2A6 * metabolismus   genetika   MeSH
• játra * metabolismus   MeSH
• kur domácí metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• transkripční faktor AP-1 * metabolismus   genetika   MeSH
• transkripční faktor Sp1 * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aflatoxin B1 * MeSH
• cytochrom P-450 CYP1A1 * MeSH
• cytochrom P450 CYP2A6 * MeSH
• transkripční faktor AP-1 * MeSH
• transkripční faktor Sp1 * MeSH

The most common type of aflatoxin (AFT) found in nature is aflatoxin B1 (AFB1). This micotoxin is extremely hepatotoxic and carcinogenic to mammals, with acute and chronic effects. It is believed that this could be related to the capacity of AFB1 and its metabolites in inhibiting the enzyme acetylcholinesterase (AChE). In a previous work, we performed an inedited theoretical investigation on the binding modes of these molecules on the peripheral anionic site (PAS) of human AChE (HssAChE), revealing that the metabolites can also bind in the PAS in the same way as AFB1. Here, we investigated the binding modes of these compounds on the catalytic anionic site (CAS) of HssAChE to compare the affinity of the metabolites for both binding sites as well as verify which is the preferential one. Our results corroborated with experimental studies pointing to AFB1 and its metabolites as mixed-type inhibitors, and pointed to the residues relevant for the stabilization of these compounds on the CAS of HssAChE.

• Klíčová slova
• acetylcholinesterase, aflatoxin B1, catalytic anionic site, metabolites,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• aflatoxin B1 chemie   metabolismus   MeSH
• cholinesterasové inhibitory chemie   metabolismus   MeSH
• hydrofobní a hydrofilní interakce MeSH
• katalytická doména MeSH
• lidé MeSH
• molekulární modely * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aflatoxin B1 MeSH
• cholinesterasové inhibitory MeSH