Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, United Kingdom.
Drug Metab Rev. 2011 May;43(2):92-137. doi: 10.3109/03602532.2011.567391.
Glutathione transferase (GST) isoezymes are encoded by three separate families of genes (designated cytosolic, microsomal and mitochondrial transferases), with distinct evolutionary origins, that provide mammalian species with protection against electrophiles and oxidative stressors in the environment. Members of the cytosolic class Alpha, Mu, Pi and Theta GST, and also certain microsomal transferases (MGST2 and MGST3), are up-regulated by a diverse spectrum of foreign compounds typified by phenobarbital, 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, pregnenolone-16α-carbonitrile, 3-methylcholanthrene, 2,3,7,8-tetrachloro-dibenzo-p-dioxin, β-naphthoflavone, butylated hydroxyanisole, ethoxyquin, oltipraz, fumaric acid, sulforaphane, coumarin, 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole, 12-O-tetradecanoylphorbol-13-acetate, dexamethasone and thiazolidinediones. Collectively, these compounds induce gene expression through the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), the aryl hydrocarbon receptor (AhR), NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ) and CAATT/enhancer binding protein (C/EBP) β. The microsomal T family includes 5-lipoxygenase activating protein (FLAP), leukotriene C(4) synthase (LTC4S) and prostaglandin E(2) synthase (PGES-1), and these are up-regulated by tumour necrosis factor-α, lipopolysaccharide and transforming growth factor-β. Induction of genes encoding FLAP, LTC4S and PGES-1 is mediated by the transcription factors C/EBPα, C/EBPδ, C/EBPϵ, nuclear factor-κB and early growth response-1. In this article we have reviewed the literature describing the mechanisms by which cytosolic and microsomal GST are up-regulated by xenobiotics, drugs, cytokines and endotoxin. We discuss cross-talk between the different induction mechanisms, and have employed bioinformatics to identify cis-elements in the upstream regions of GST genes to which the various transcription factors mentioned above may be recruited.
谷胱甘肽转移酶（GST）同工酶由三个独立的基因家族（分别为胞质、微粒体和线粒体转移酶）编码，具有不同的进化起源，为哺乳动物物种提供了对环境中亲电体和氧化应激源的保护。胞质类 Alpha、Mu、Pi 和 Theta GST 的成员，以及某些微粒体转移酶（MGST2 和 MGST3），被各种外源化合物上调，这些化合物的典型代表有苯巴比妥、1,4-双[2-(3,5-二氯吡啶氧基)]苯、孕烯醇酮-16α-氰化物、3-甲基胆蒽、2,3,7,8-四氯二苯并-p-二恶英、β-萘黄酮、丁羟甲苯、乙氧喹、奥曲肽、富马酸、萝卜硫素、香豆素、1-[2-氰基-3,12-二氧代-oleana-1,9(11)-二烯-28-酰基]咪唑、12-O-十四烷酰佛波醇-13-乙酸酯、地塞米松和噻唑烷二酮。这些化合物通过组成型雄烷受体（CAR）、孕烷 X 受体（PXR）、芳烃受体（AhR）、核因子-E2 相关因子 2（Nrf2）、过氧化物酶体增殖物激活受体-γ（PPARγ）和 CAATT/增强子结合蛋白（C/EBP）β 共同诱导基因表达。微粒体 T 家族包括 5-脂氧合酶激活蛋白（FLAP）、白三烯 C（4）合酶（LTC4S）和前列腺素 E（2）合酶（PGES-1），这些酶被肿瘤坏死因子-α、脂多糖和转化生长因子-β 上调。FLAP、LTC4S 和 PGES-1 基因的诱导由转录因子 C/EBPα、C/EBPδ、C/EBPε、核因子-κB 和早期生长反应-1 介导。在本文中，我们综述了描述胞质和微粒体 GST 被外源性物质、药物、细胞因子和内毒素上调的机制的文献。我们讨论了不同诱导机制之间的串扰，并运用生物信息学方法识别 GST 基因上游区域的顺式元件，上述各种转录因子可能被招募到这些顺式元件中。
