De Luca C, Scordo G, Cesareo E, Raskovic D, Genovesi G, Korkina L
Laboratory of Tissue Engineering & Cutaneous Pathophysiology, Istituto Dermopatico dell'Immacolata, Rome, Italy.
Indian J Exp Biol. 2010 Jul;48(7):625-35.
Inherited or acquired impairment of xenobiotics metabolism is a postulated mechanism underlying environment-associated pathologies such as multiple chemical sensitivity, fibromyalgia, chronic fatigue syndrome, dental amalgam disease, and others, also collectively named idiopathic environmental intolerances (IEI). In view of the poor current knowledge of their etiology and pathogenesis, and the absence of recognised genetic and metabolic markers of the diseases. They are often considered "medically unexplained syndromes",. These disabling conditions share the features of polysymptomatic multi-organ syndromes, considered by part of the medical community to be aberrant responses triggered by exposure to low-dose organic and inorganic chemicals and metals, in concentrations far below average reference levels admitted for environmental toxicants. A genetic predisposition to altered biotransformation of environmental chemicals, drugs, and metals, and of endogenous low-molecular weight metabolites, caused by polymorphisms of genes coding for xenobiotic metabolizing enzymes, their receptors and transcription factors appears to be involved in the susceptibility to these environment-associated pathologies, along with epigenetic factors. Free radical/antioxidant homeostasis may also be heavily implicated, indirectly by affecting the regulation of xenobiotic metabolizing enzymes, and directly by causing increased levels of oxidative products, implicated in the chronic damage of cells and tissues, which is in part correlated with clinical symptoms. More systematic studies of molecular epidemiology, toxico- and pharmaco-genomics, elucidating the mechanisms of regulation, expression, induction, and activity of antioxidant/detoxifying enzymes, and the possible role of inflammatory mediators, promise a better understanding of this pathologically increased sensitivity to low-level chemical stimuli, and a solid basis for effective individualized antioxidant- and/or chelator-based treatments.
外源性物质代谢的遗传性或获得性损伤是一种假定的机制，是诸如多重化学物质敏感、纤维肌痛、慢性疲劳综合征、牙科汞合金病等与环境相关疾病的潜在病因，这些疾病也统称为特发性环境不耐受（IEI）。鉴于目前对其病因和发病机制了解不足，且缺乏公认的疾病遗传和代谢标志物，它们常被视为“医学上无法解释的综合征”。这些致残性疾病具有多症状多器官综合征的特征，部分医学界人士认为这是由接触低剂量有机和无机化学物质及金属引发的异常反应，其浓度远低于环境毒物允许的平均参考水平。由编码外源性物质代谢酶、其受体和转录因子的基因多态性导致的环境化学物质、药物和金属以及内源性低分子量代谢物生物转化改变的遗传易感性，似乎与这些与环境相关疾病的易感性有关，同时还涉及表观遗传因素。自由基/抗氧化剂稳态也可能密切相关，一方面通过影响外源性物质代谢酶的调节间接起作用，另一方面通过导致氧化产物水平升高直接起作用，氧化产物与细胞和组织的慢性损伤有关，这部分与临床症状相关。分子流行病学、毒理基因组学和药物基因组学的更系统研究，阐明抗氧化/解毒酶的调节、表达、诱导和活性机制以及炎症介质的可能作用，有望更好地理解这种对低水平化学刺激的病理敏感性增加，并为基于抗氧化剂和/或螯合剂的有效个体化治疗奠定坚实基础。
