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Nrf2是调控解毒、抗氧化、抗炎等细胞保护机制的重要转录因子——它的活性可被保健食物及其他因素增强

Martin L Pall, Stephen Levine

华盛顿州立大学，波特兰，俄勒冈州 97232-3312，美国；Allergy Research Group，阿拉米达，加利福尼亚州 94502，美国

摘要

转录因子Nrf2 (nuclear factor erythroid-2-related factor 2)可激活人类基因组中500多种基因的转录，这些基因大多数具有细胞保护功能。Nrf2通过解毒机制产生细胞保护作用，这些机制增强了有害异物和有毒金属的解毒和排泄。Nrf2经20多种基因的作用来增加高度协调的抗氧化活性；Nrf2也具有重要的抗炎作用；Nrf2促进线粒体的生物合成抑或提高线粒体功能；Nrf2增强细胞自噬以清除毒性蛋白的聚集体和功能异常的细胞器。有益健康的营养素和其他因素，包括酚类抗氧化剂、γ-和δ-生育酚和三烯生育酚、长链Ω-3脂肪酸DHA和EPA、类胡萝卜素(其中番茄红素可能活性最强)、十字花科蔬菜中的异硫氰酸酯、葱蒜类蔬菜中的硫化物、及萜类化合物，至少部分是通过增加Nrf2活性起作用的。其他一些有益健康并增加Nrf2活性的因素包括低水平的氧化应激[毒物兴奋效应(hormesis)]、锻炼和热量限制。现已发现，增加Nrf2活性可预防和/或治疗模型动物和/或人类许多慢性炎症性疾病，包括各种心血管疾病、肾脏疾病、肺脏疾病、中毒性肝损伤疾病、癌症(预防)、糖尿病/代谢综合征/肥胖、败血症、自身免疫性疾病、炎性肠病、HIV/AIDS及癫痫。较少证据提示增加Nrf2活性可降低其他16种疾病的风险，这些疾病中的大多数可能是NO/ONOO−环有关的疾病，而Nrf2可削弱NO/ONOO−环元素的多种作用。已知最健康的饮食(地中海和冲绳地区的传统饮食)富含促进Nrf2活性的营养素，这就像我们的祖先在旧石器时代的饮食一样。Nrf2是否同时具有延长寿命和促进健康的作用是有争议的。Nrf2活性过度的可能负面作用也被讨论。Nrf2不是一个灵丹妙药，但可能对于促进健康非常重要，特别是对于那些日常暴露于有毒化学药品的人。

关键词： 亲电体和氧化剂; Keap1; ERK; PI3K; GSK-3β; AMPK; 蛋白激酶C和G; 有害异物和有毒金属; 解毒; 慢性炎症性疾病; 氧化和硝化应激

分类号：Q75; R151.4

Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors

Martin L Pall, Stephen Levine

Washington State University, Portland, Oregon 97232-3312, USA； Allergy Research Group, Alameda, California 94502, USA

Abstract

The transcription factor Nrf2, nuclear factor erythroid-2-related factor 2, activates the transcription of over 500 genes in the human genome, most of which have cytoprotective functions. Nrf2 produces cytoprotection by detoxification mechanisms leading to increased detoxification and excretion of both organic xenobiotics and toxic metals; its action via over two dozen genes increases highly coordinated antioxidant activities; it produces major anti-inflammatory changes; it stimulates mitochondrial biogenesis and otherwise improves mitochondrial function; and it stimulates autophagy, removing toxic protein aggregates and dysfunctional organelles. Health-promoting nutrients and other factors act, at least in part by raising Nrf2 including: many phenolic antioxidants; gamma- and delta-tocopherols and tocotrienols; long chain omega-3 fatty acids DHA and EPA; many carotenoids of which lycopene may be the most active; isothiocyanates from cruciferous vegetables; sulfur compounds from allium vegetables; terpenoids. Other health promoting, Nrf2 raising factors include low level oxidative stress (hormesis), exercise and caloric restriction. Raising Nrf2 has been found to prevent and/or treat a large number of chronic inflammatory diseases in animal models and/or humans including various cardiovascular diseases, kidney diseases, lung diseases, diseases of toxic liver damage, cancer (prevention), diabetes/metabolic syndrome/obesity, sepsis, autoimmune diseases, inflammatory bowel disease, HIV/AIDS and epilepsy. Lesser evidence suggests that raising Nrf2 may lower 16 other diseases. Many of these diseases are probable NO/ONOO− cycle diseases and Nrf2 lowers effects of NO/ONOO− cycle elements. The most healthful diets known, traditional Mediterranean and Okinawan, are rich in Nrf2 raising nutrients as apparently was the Paleolithic diet that our ancestors ate. Modern diets are deficient in such nutrients. Nrf2 is argued to be both lifespan and healthspan extending. Possible downsides to too much Nrf2 are also discussed. Nrf2 is not a magic bullet but is likely to be of great importance in health promotion, particularly in those regularly exposed to toxic chemicals.

Key words: electrophiles and oxidants; Keap1; ERK; PI3K; GSK-3β; AMPK; protein kinases C and G; toxic xenobiotics and toxic metals; detoxification; chronic inflammatory diseases; oxidative and nitrosative stress

收稿日期：2014-07-28　　录用日期：2014-09-22

通讯作者：Martin L Pall　　E-mail: martin_pall@wsu.edu

引用本文：

Martin L Pall, Stephen Levine. Nrf2是调控解毒、抗氧化、抗炎等细胞保护机制的重要转录因子——它的活性可被保健食物及其他因素增强[J]. 生理学报 2015; 67 (1): 1-18.

Martin L Pall, Stephen Levine. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Acta Physiol Sin 2015; 67 (1): 1-18 (in Chinese with English abstract).