title: Cytochrome P450 2A13 mediates aflatoxin B1-induced cytotoxicity and apoptosis in human bronchial epithelial cells.
abstract: Cytochrome P450 (CYP) 2A13 is mainly expressed in the respiratory system and has the ability to metabolize aflatoxin B(1) (AFB(1)). However, the role of CYP2A13-mediated AFB(1) metabolism and its consequences in human lung epithelial cell is not clear. Therefore, the objectives of this study were to investigate the significance of CYP2A13 in AFB(1)-induced cytotoxicity, DNA adducts, and apoptosis. To achieve these objectives, CYP2A13 was stably over-expressed in immortalized human bronchial epithelial BEAS-2B cells (B-2A13) and its significance in AFB(1)-induced cytotoxicity, DNA adducts, and apoptosis was compared to cells with stably expression of CYP1A2 (B-1A2), the predominant AFB(1) metabolizing enzyme in liver, as well as CYP2A6 (B-2A6) as controls. AFB(1) induced B-2A13 cytotoxicity and apoptosis in a dose- and time-dependent manner. The cytotoxic and apoptotic effects of AFB(1) were significantly remarkable in B-2A13 cells than those of B-1A2 and B-2A6 cells. The increased expression of pro-apoptotic proteins, such as C-PARP, C-caspase-3, and Bax, and decreased expression of anti-apoptotic proteins, such as caspase-3, Bcl-2, and p-Bad further confirmed the data of AFB(1)-induced cytotoxicity and apoptosis. Furthermore, increased DNA adduct was observed in B-2A13 after AFB(1) treatment as compared to B-1A2 cells and B-2A6 cells. Finally, treatment with nicotine, a competitor of AFB(1), and 8-methoxypsoralen (8-MOP), an inhibitor of CYP enzyme, further confirm the critical role of CYP2A13 in AFB(1)-induced cytotoxicity and apoptosis. Collectively, these findings suggest adverse effects of AFB(1) in respiratory diseases mediated by CYP2A13.
authors: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 210029, PR China.
authors: Xue-Jiao
authors: XJ
authors: Yang
authors: Hui-Yuan
authors: HY
authors: Lu
authors: Zi-Yin
authors: ZY
authors: Li
authors: Qian
authors: Q
authors: Bian
authors: Liang-Lin
authors: LL
authors: Qiu
authors: Zhong
authors: Z
authors: Li
authors: Qizhan
authors: Q
authors: Liu
authors: Jianmin
authors: J
authors: Li
authors: Xinru
authors: X
authors: Wang
authors: Shou-Lin
authors: SL
authors: Wang
mesh_terms: D016604:Aflatoxin B1 / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018736:DNA Adducts / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010957:Plasmids; D013997:Time Factors; D014162:Transfection
chemical_list: D018736:DNA Adducts; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human