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摘要
内分泌系统是一个主要的通信系统,在体内参与生殖系统的维护、胎儿发育、成长、成熟、能源生产和新陈代谢。生物体的内分泌系统通过分泌多种激素,使身体保持体内平衡,应对外部刺激和各种发育过程。这些过程的产生是通过复杂的信号级联,多个可调节信号的站点实现的。内分泌干扰物质(edc)影响内分泌系统,可通过模拟自然产生的激素的作用,抑制天然激素的作用,改变功能和合成激素受体,或改变合成、运输、代谢来消除荷尔蒙。人类和野生动物在接触环境过程中,edc是破坏生殖发展和肿瘤形成的危险因素,这一理论已经确立。为了精确的对Edc风险评估通过生物转化过程的生物活化可能性需要被考虑,因为忽视这些机制可能会导致低估edc和/或其代谢产物对人类健康造成的负面影响。准确的风险评估应该包括:(1) 在增强内分泌干扰的情况下,edc成为具有生物活性代谢物质的可能性与增强内分泌干扰代谢物(ED)的影响;(2) edc生物转化成可能导致DNA损伤的活性代谢物的可能性。本文我们提供了一个参与edc的生物转化不同的代谢酶的概述。此外,我们描述了生物转化的细胞色素P450(cyp)、人类雌激素sulfotransferase 1 e1(SULT1E1)和选择其他二期酶,如何导致生物活性代谢产物的形成。本文主要关注CYP与SULT-mediated生物活化雌激素edc并总结了关于这个主题我们的观点。同时显示包括生物活化和生物转化过程的重要性,提高风险评估方法的可行性。
关键词: 生物活化,生物转化,细胞色素P450,内分泌失调,内分泌干扰物,雌激素受体,活性中间体,硫转移酶
Current Medicinal Chemistry
Title:Biotransformation of Endocrine Disrupting Compounds by Selected Phase I and Phase II Enzymes – Formation of Estrogenic and Chemically Reactive Metabolites by Cytochromes P450 and Sulfotransferases
Volume: 22 Issue: 4
Author(s): J. Reinen and N.P.E. Vermeulen
Affiliation:
关键词: 生物活化,生物转化,细胞色素P450,内分泌失调,内分泌干扰物,雌激素受体,活性中间体,硫转移酶
摘要: The endocrine system is a major communication system in the body and is involved in maintenance of the reproductive system, fetal development, growth, maturation, energy production, and metabolism,. The endocrine system responds to the needs of an organism by secreting a wide variety of hormones that enable the body to maintain homeostasis, to respond to external stimuli, and to follow various developmental programs. This occurs through complex signalling cascades,with multiple sites at which the signals can be regulated. Endocrine disrupting compounds (EDCs) affect the endocrine system by simulating the action of the naturally produced hormones, by inhibiting the action of natural hormones, by changing the function and synthesis of hormone receptors, or by altering the synthesis, transport, metabolism, and elimination of hormones. It has been established that exposure to environmental EDCs is a risk factor for disruption of reproductive development and oncogenesis in both humans and wildlife. For accurate risk assessment of EDCs, the possibility of bioactivation through biotransformation processes needs to be included since neglecting these mechanisms may lead to undervaluation of adverse effects on human health caused by EDCs and/or their metabolites. This accurate risk assessment should include: (1) possibility of EDCs to be bioactivated into metabolites with enhanced endocrine disruption (ED) effects, and (2) possibility of EDCs to be biotransformed into reactive metabolites that may cause DNA damage. Here, we present an overview of different metabolic enzymes that are involved in the biotransformation of EDCs. In addition, we describe how biotransformation by Cytochromes P450 (CYPs), human estrogen sulfotransferase 1E1 (SULT1E1) and selected other phase II enzymes, can lead to the formation of bioactive metabolites. This review mainly focuses on CYP- and SULT-mediated bioactivation of estrogenic EDCs and summarizes our views on this topic while also showing the importance of including bioactivation and biotransformation processes for improved risk assessment strategies.
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J. Reinen and N.P.E. Vermeulen , Biotransformation of Endocrine Disrupting Compounds by Selected Phase I and Phase II Enzymes – Formation of Estrogenic and Chemically Reactive Metabolites by Cytochromes P450 and Sulfotransferases, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666140916123022
DOI https://dx.doi.org/10.2174/0929867321666140916123022 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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