O'Brien Evelyn, Dietrich Daniel R
Environmental Toxicology, University of Konstanz, Germany.
Crit Rev Toxicol. 2005 Jan;35(1):33-60. doi: 10.1080/10408440590905948.
The mycotoxin ochratoxin A (OTA) has been linked to the genesis of several disease states in both animals and humans. It has been described as nephrotoxic, carcinogenic, teratogenic, immunotoxic, and hepatotoxic in laboratory and domestic animals, as well as being thought to be the probable causal agent in the development of nephropathies (Balkan Endemic Nephropathy, BEN and Chronic Interstitial Nephropathy, CIN) and urothelial tumors in humans. As a result, several international agencies are currently attempting to define safe legal limits for OTA concentration in foodstuffs (e.g., grain, meat, wine, and coffee), in processed foods, and in animal fodder. In order to achieve this goal, an accurate risk assessment of OTA toxicity including mechanistic and epidemiological studies must be carried out. Ochratoxin has been suggested by various researchers to mediate its toxic effects via induction of apoptosis, disruption of mitochondrial respiration and/or the cytoskeleton, or, indeed, via the generation of DNA adducts. Thus, it is still unclear if the predominant mechanism is of a genotoxic or an epigenetic nature. One aspect that is clear, however, is that the toxicity of OTA is subject to and characterized by large species- and sex-specific differences, as well as an apparently strict structure-activity relationship. These considerations could be crucial in the investigation of OTA-mediated toxicity. Furthermore, the use of appropriate in vivo and in vitro model systems appears to be vital in the generation of relevant experimental data. The intention of this review is to collate and discuss the currently available data on OTA-mediated toxicity with particular focus on their relevance for the in vivo situation, and also to suggest possible future strategies for unlocking the secrets of ochratoxin A.
霉菌毒素赭曲霉毒素A（OTA）与动物和人类多种疾病状态的发生有关。在实验室动物和家畜中，它被描述为具有肾毒性、致癌性、致畸性、免疫毒性和肝毒性，并且被认为可能是人类肾病（巴尔干地方性肾病，BEN和慢性间质性肾病，CIN）以及尿路上皮肿瘤发展的病因。因此，目前几个国际机构正在尝试确定食品（如谷物、肉类、葡萄酒和咖啡）、加工食品和动物饲料中OTA浓度的安全法定限值。为了实现这一目标，必须对OTA毒性进行准确的风险评估，包括机制研究和流行病学研究。多位研究人员提出，赭曲霉毒素通过诱导细胞凋亡、破坏线粒体呼吸和/或细胞骨架，或者实际上通过产生DNA加合物来介导其毒性作用。因此，目前仍不清楚主要机制是遗传毒性还是表观遗传性质。然而，有一点是明确的，即OTA的毒性存在很大的物种和性别差异，以及明显严格的构效关系。这些因素在研究OTA介导的毒性时可能至关重要。此外，使用合适的体内和体外模型系统对于生成相关实验数据似乎至关重要。本综述的目的是整理和讨论目前关于OTA介导毒性的可用数据，特别关注它们与体内情况的相关性，并提出未来解开赭曲霉毒素A秘密的可能策略。
