Mulder Jeanne E, Bondy Genevieve S, Mehta Rekha, Massey Thomas E
Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University Kingston, Ontario, Canada K7L 3N6.
Toxicology Research Division, 2202D, Bureau of Chemical Safety, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, K1A 0K9 Canada.
Mutat Res. 2015 Mar;773:63-8. doi: 10.1016/j.mrfmmm.2015.01.015. Epub 2015 Jan 30.
Aflatoxin B1 (AFB1) is produced by species of Aspergillus, and is a known human carcinogen. AFB1-induced oxidative DNA damage, specifically 8-hydroxy-2-deoxyguanosine (8-OHdG) lesions, has been demonstrated in both animal models and in humans, and is repaired by base excision repair (BER). The tumour suppressor gene p53 is implicated in the regulation of DNA repair, and heterozygous p53 knockouts have an attenuated nucleotide excision repair response to AFB1. Male heterozygous p53 knockout mice and their wild-type controls were exposed to 0, 0.2 or 1.0ppm AFB1 for 26 weeks in their diet. BER activity of lung and liver was assessed with an in vitro assay, using 8-OHdG-damaged plasmid DNA as a substrate. BER activity did not differ between livers or lungs from untreated wild-type versus heterozygous p53 knockout mice. In wild-type mice, repair was 65% lower in liver extracts from mice exposed to 1.0ppm AFB1 than in liver extracts from mice exposed to 0.2ppm AFB1 (p<0.05), but not significantly lower than that in liver extracts from control mice. AFB1 did not affect BER in lung extracts from wild-type mice, or in lung and liver extracts from heterozygous p53 knockout mice. In liver and lung, AFB1 exposure did not alter levels of 8-oxoguanine glycosylase protein, a key enzyme in the repair of 8-OHdG, and did not cause hepatotoxicity, as indicated by plasma alanine aminotransferase levels. In conclusion, chronic exposure to AFB1 did not affect BER in lungs or livers of heterozygous p53 knockout mice. BER activity was lower in livers from p53 wild type mice exposed to 1.0ppm AFB1 versus those exposed to 0.2ppm AFB1, an effect that was not attributable to liver cell death or altered levels of 8-oxoguanine glycosylase.
黄曲霉毒素B1（AFB1）由曲霉菌种产生，是一种已知的人类致癌物。在动物模型和人类中均已证实，AFB1可诱导氧化性DNA损伤，特别是8-羟基-2'-脱氧鸟苷（8-OHdG）损伤，且该损伤由碱基切除修复（BER）进行修复。肿瘤抑制基因p53参与DNA修复的调控，杂合型p53基因敲除小鼠对AFB1的核苷酸切除修复反应减弱。雄性杂合型p53基因敲除小鼠及其野生型对照在饮食中接触0、0.2或1.0ppm的AFB1，持续26周。以8-OHdG损伤的质粒DNA为底物，通过体外试验评估肺和肝脏的BER活性。未处理的野生型小鼠与杂合型p53基因敲除小鼠的肝脏或肺脏之间，BER活性没有差异。在野生型小鼠中，接触1.0ppm AFB1的小鼠肝脏提取物中的修复率比接触0.2ppm AFB1的小鼠肝脏提取物低65%（p<0.05），但并不显著低于对照小鼠肝脏提取物中的修复率。AFB1对野生型小鼠肺提取物或杂合型p53基因敲除小鼠的肺和肝脏提取物中的BER没有影响。在肝脏和肺中，AFB1暴露未改变8-氧鸟嘌呤糖基化酶蛋白的水平，该蛋白是修复8-OHdG的关键酶，并且血浆丙氨酸转氨酶水平表明未引起肝毒性。总之，长期接触AFB1对杂合型p53基因敲除小鼠的肺或肝脏中的BER没有影响。接触1.0ppm AFB1的p53野生型小鼠肝脏中的BER活性低于接触0.2ppm AFB1的小鼠，这种效应并非归因于肝细胞死亡或8-氧鸟嘌呤糖基化酶水平的改变。
