Cytochrome P450 2A13 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1-induced DNA damage

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• 作者：Xuejiao Yang^a ; ^b ; ¹ ; Zhan Zhang^a ; ¹ ; Xichen Wang^a ; Yun Wang^a ; Xiaoming Zhang^a ; Huiyuan Lu^a ; Shou-Lin Wang^a ; ^{wangshl@njmu.edu.cn}
• 关键词：CYP450 ; Cytochrome P450 ; AFB1 ; Aflatoxin B1 ; BEAS-2B cells ; immortalized human bronchial epithelial cells ; B-2A13 cells ; BEAS-2B cells stably expressing CYP2A13 ; AFB1-FAPY ; AFB1-formamidopyrimidine ; AFB1-N7-Gua ; trans-8 ; 9-dihydro-8-(N7-guanyl)-9-hydroxyaf
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：270
• 期：2
• 页码：114-121
• 全文大小：1312 K

文摘

Cytochrome P450 2A13 (CYP2A13) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 (AFB1). Our previous study suggested that CYP2A13 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells (BEAS-2B). However, the role of CYP2A13 in AFB1-induced DNA damage is unclear. Using BEAS-2B cells that stably express CYP2A13 (B-2A13), CYP1A2 (B-1A2), and CYP2A6 (B-2A6), we compared their effects in AFB1-induced DNA adducts, DNA damage, and cell cycle changes. BEAS-2B cells that were transfected with vector (B-vector) were used as a control. The results showed that AFB1 (5-80 nM) dose- and time-dependently induced DNA damage in B-2A13 cells. AFB1 at 10 and 80 nM significantly augmented this effect in B-2A13 and B-1A2 cells, respectively. B-2A6 cells showed no obvious DNA damage, similar to B-vector cells and the vehicle control. Similarly, compared with B-vector, B-1A2 or B-2A6 cells, B-2A13 cells showed more sensitivity in AFB1-induced ¦ÃH2AX expression, DNA adduct 8-hydroxy-deoxyguanosine formation, and S-phase cell-cycle arrest. Furthermore, AFB1 activated the proteins related to DNA damage responses, such as ATM, ATR, Chk2, p53, BRCA1, and H2AX, rather than the proteins related to DNA repair. These effects could be almost completely inhibited by 100 ¦ÌM nicotine (a substrate of CYP2A13) or 1 ¦ÌM 8-methoxypsoralen (8-MOP; an inhibitor of CYP enzyme). Collectively, these findings suggest that CYP2A13 plays an important role in low-concentration AFB1-induced DNA damage, possibly linking environmental airborne AFB1 to genetic injury in human respiratory system.