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Cytochrome P450 2A13 is an efficient enzyme in metabolic activation of aflatoxin G1 in human bronchial epithelial cells

  • Toxicokinetics and Metabolism
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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.

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Abbreviations

CYP:

Cytochrome P450

AFG1:

Aflatoxin G1

AFB1:

Aflatoxin B1

8-MOP:

8-Methoxypsoralen

BEAS-2B:

Immortalized human bronchial epithelial cells

B-2A13:

BEAS-2B cells stably expressing CYP2A13

8-OHdG:

8-Hydroxydeoxyguanosine

DSB:

Double strand break

ATM:

Ataxia telangiectasia mutated

ATR:

Ataxia telangiectasia and Rad3 related

Chk1/2:

Checkpoint kinase 1/2

HR:

Homologous recombination

NHEJ:

Nonhomologous end joining

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Acknowledgments

This work was supported by National Natural Science Foundation of China (81172695, 30771782), National 973 program (2009CB941701), Six Talents Peak Project of Jiangsu Province (DG216D5047), and a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), China.

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Authors and Affiliations

  1. Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 818 East Tianyuan Rd., Nanjing, 211166, China

    Zhan Zhang, Xuejiao Yang, Yun Wang, Xichen Wang, Huiyuan Lu, Xiaoming Zhang, Xue Xiao, Shushu Li, Xinru Wang & Shou-Lin Wang

  2. Jiaojiang District Center for Disease Control and Prevention of Taizhou, 518 Jingdong Rd., Taizhou, 318000, China

    Xuejiao Yang

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  1. Zhan Zhang
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  2. Xuejiao Yang
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  10. Shou-Lin Wang
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Corresponding author

Correspondence to Shou-Lin Wang.

Additional information

Zhan Zhang and Xuejiao Yang have contributed equally to this study.

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Zhang, Z., Yang, X., Wang, Y. et al. Cytochrome P450 2A13 is an efficient enzyme in metabolic activation of aflatoxin G1 in human bronchial epithelial cells. Arch Toxicol 87, 1697–1707 (2013). https://doi.org/10.1007/s00204-013-1108-3

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  • DOI: https://doi.org/10.1007/s00204-013-1108-3

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