title: Cytochrome P450 2A13 is an efficient enzyme in metabolic activation of aflatoxin G1 in human bronchial epithelial cells.
abstract: Cytochrome P450 2A13 (CYP2A13) is an extrahepatic enzyme that mainly expresses in human respiratory system, and it is reported to mediate the metabolic activation of aflatoxin B1. Due to the structural similarity, AFG1 is predicted to be metabolized by CYP2A13. However, the role of CYP2A13 in metabolic activation of AFG1 is unclear. In present study, human bronchial epithelial cells that stably express CYP2A13 (B-2A13) were used to conduct the effects of AFG1 on cytotoxicity, apoptosis, DNA damages, and their response protein expression. Low concentrations of AFG1 induced significant cytotoxicity and apoptosis, which was consistent with the increased expressions of pro-apoptotic proteins, such as C-PARP and C-caspase-3. In addition, AFG1 increased 8-OHdG and γH2AX in the nuclies and induced S phase arrest and DNA damage in B-2A13 cells, and the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and γH2AX, were activated. All the above effects were inhibited by nicotine (a substrate of CYP2A13) or 8-MOP (an inhibitor of CYP enzymes), confirming that CYP2A13 mediated the AFG1-induced cytotoxicity and DNA damages. Collectively, our findings first demonstrate that CYP2A13 might be an efficient enzyme in metabolic activation of AFG1 and helps provide a new insight into adverse effects of AFG1 in human respiratory system.
authors.affiliation: Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 818 East Tianyuan Rd., Nanjing, 211166, China.
authors.forename: Zhan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xuejiao
authors.initials: X
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Xichen
authors.initials: X
authors.lastname: Wang
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Lu
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.forename: Shushu
authors.initials: S
authors.lastname: Li
authors.forename: Xinru
authors.initials: X
authors.lastname: Wang
authors.forename: Shou-Lin
authors.initials: SL
authors.lastname: Wang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D016604:Aflatoxin B1 / Q000819:agonists / Q000378:metabolism / Q000633:toxicity; D000348:Aflatoxins / Q000819:agonists / Q000378:metabolism* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D001711:Biotransformation; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D004249:DNA Damage; D003849:Deoxyguanosine / Q000819:agonists / Q000031:analogs & derivatives / Q000378:metabolism; D006657:Histones / Q000819:agonists / Q000378:metabolism; D006801:Humans; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity
chemical_list: D000348:Aflatoxins; C468783:H2AX protein, human; D006657:Histones; D011994:Recombinant Proteins; C027955:aflatoxin G1; D000080242:8-Hydroxy-2'-Deoxyguanosine; D016604:Aflatoxin B1; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; D003849:Deoxyguanosine