Mally Angela, Dekant Wolfgang
Department of Toxicology, University of Würzburg, Germany.
Mol Nutr Food Res. 2009 Apr;53(4):467-78. doi: 10.1002/mnfr.200800149.
The mycotoxin ochratoxin A (OTA) is a potent renal carcinogen in rodents. OTA is only slowly eliminated due to high affinity to plasma proteins and inefficient biotransformation. A number of mechanisms have been proposed to account for renal tumor formation. DNA adduct formation, mainly based on the( 32)P-postlabeling assay, was postulated as a mode of action (MoA). However, studies using radiolabeled OTA or MS failed to demonstrate formation of OTA-derived DNA-adducts. While some studies have demonstrated generation of oxidative stress by OTA, the oxidative stress response appears to be not very pronounced and therefore may not explain the high potency of OTA in rodents. A number of recent investigations support the hypothesis that OTA causes disruption of mitosis resulting in blocked or asymmetric cell division. This may present an increased risk of aneuploidy acquisition and may play a critical role in OTA-induced tumor formation. The absence of DNA-adducts derived from OTA supports a thresholded MoA, and a tolerable weekly intake (TWI) of 120 ng OTA/kg bw has been derived by the European Food Safety Authority. The estimated intake of OTA in Europe is below this TWI for most of the population.
霉菌毒素赭曲霉毒素A（OTA）是啮齿动物体内一种强效的肾致癌物。由于其对血浆蛋白的高亲和力和低效的生物转化作用，OTA的消除速度很慢。人们提出了多种机制来解释肾肿瘤的形成。基于（32）P后标记分析的DNA加合物形成被假定为一种作用模式（MoA）。然而，使用放射性标记的OTA或质谱分析的研究未能证明OTA衍生的DNA加合物的形成。虽然一些研究表明OTA会产生氧化应激，但氧化应激反应似乎并不十分明显，因此可能无法解释OTA在啮齿动物体内的高致癌性。最近的一些研究支持了这样一种假设，即OTA会导致有丝分裂紊乱，从而导致细胞分裂受阻或不对称。这可能会增加获得非整倍体的风险，并可能在OTA诱导的肿瘤形成中起关键作用。缺乏源自OTA的DNA加合物支持了一种阈值作用模式，欧洲食品安全局得出的可耐受每周摄入量（TWI）为120 ng OTA/kg体重。在欧洲，大多数人群的OTA估计摄入量低于这个TWI。
