Istituto Dermopatico dell'Immacolata, Rome, Italy.
Curr Drug Metab. 2009 Oct;10(8):914-31. doi: 10.2174/138920009790274568.
Chemical defensive system consisting of bio-sensoring, transmitting, and responsive elements has been evolved to protect multi-cellular organisms against environmental chemical insults (xenobiotics) and to maintain homeostasis of endogenous low molecular weight metabolites (endobiotics). Both genetic and epigenetic defects of the system in association with carcinogenesis and individual sensitivity to anti-tumor therapies have been intensely studied. Recently, several non-tumor human pathologies with evident environmental components such as rather rare functional syndromes (multiple chemical sensitivity, chronic fatigue, Persian Gulf, and fibromyalgia now collectively labeled as idiopathic environmental intolerances) and common diseases (vitiligo and systemic lupus erythematosus) have become subjects of the research on the impaired metabolism and detoxification of xenobiotics and endogenous toxins. Here, we collected and critically reviewed epidemiological, genetic, and biochemical data on the involvement and possible role of cytochrome P450 super family enzymes, glutathione-S-transferase isozymes, catechol-O-methyl-transferase, UDP-glucuronosyl transferases, and proteins detoxifying inorganic and organic peroxides (catalase, glutathione peroxidase, and peroxiredoxin) in the above pathologies. Genetic predisposition assessed mainly by single nucleotide polymorphism and gene expression analyses revealed correlations between defects in genes encoding xenobiotic-metabolizing and/or detoxifying enzymes and risk/severity of these syndromes/diseases. Proteome analysis identified abnormal expression of the enzymes. Their functions were affected epigenetically leading to metabolic impairment and, as a consequence, to the negative health outcomes shared by some of these pathologies. Data obtained so far suggest that distinct components of the chemical defensive system could be suitable molecular targets for future pathogenic therapies.
化学防御系统由生物感应、传递和响应元件组成，旨在保护多细胞生物免受环境化学物质（外源性化学物质）的侵害，并维持内源性低分子量代谢物（内源性物质）的内稳态。该系统的遗传和表观遗传缺陷与肿瘤发生以及个体对肿瘤治疗的敏感性有关，已受到广泛研究。最近，一些与环境因素明显相关的非肿瘤人类病理，如罕见的功能性综合征（多种化学物质敏感、慢性疲劳、波斯湾和纤维肌痛，现在统称为特发性环境不耐受）和常见疾病（白癜风和系统性红斑狼疮），已成为研究外源性化学物质和内源性毒素代谢和解毒受损的对象。在这里，我们收集并批判性地回顾了与细胞色素 P450 超家族酶、谷胱甘肽 S-转移酶同工酶、儿茶酚-O-甲基转移酶、UDP-葡萄糖醛酸转移酶和解毒无机和有机过氧化物的蛋白质（过氧化氢酶、谷胱甘肽过氧化物酶和过氧化物酶）在上述病理中的作用的流行病学、遗传和生化数据。主要通过单核苷酸多态性和基因表达分析评估的遗传易感性显示，编码外源性物质代谢和/或解毒酶的基因缺陷与这些综合征/疾病的风险/严重程度之间存在相关性。蛋白质组分析确定了酶的异常表达。它们的功能受到表观遗传的影响，导致代谢受损，进而导致这些病理中的一些具有负面健康结果。迄今为止获得的研究数据表明，化学防御系统的不同成分可能是未来致病治疗的合适分子靶点。
