噻唑烷酸提高肝组织谷胱甘肽含量及其机制的研究
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摘要
人体不可避免的会受到不同毒物和药物的伤害,这些外源毒物和药物在体内经肝脏Ⅰ相和Ⅱ相代谢酶水解产生大量自由基和活性中间体。许多重要生命现象及疾病的发生都与活性中间体的产生有关,如机体的氧化与衰老、肝脏病变等。正常生理条件下,机体会产生相应机制来对抗活性中间体的损伤,使活性中间体和自由基在产生不断的同时也被不断的清除,维持机体平衡。但是,如果活性中间代谢物在体内过度积累,就会造成机体防御功能紊乱。肝脏是体内药物代谢的主要场所,更易受到活性代谢物的损伤。外源性药物、毒物是引发肝脏疾病的主要原因,因此备受重视。
细胞内的谷胱甘肽(L-γ-glutamyl-L-cysteinylglycine, GSH)是一种特殊的低分子量含巯基化合物,在机体防御系统中发挥着重要作用。谷胱甘肽分为氧化型和还原型两种形式,在谷胱甘肽过氧化物酶和谷胱甘肽还原酶的作用下,两种形式之间可以互相转化。谷胱甘肽既可以通过直接释放巯基基团起到解毒的作用,也可以作为谷胱甘肽过氧化物酶(glutathione peroxidase, GPx)和谷胱甘肽-S转移酶(glutathione S-transferase, GST)的底物来间接地发挥作用。细胞内谷胱甘肽的过度消耗会引起多种连锁反应,如细胞凋亡,氧化还原状态改变,组织功能异常,甚至会诱发多种疾病,如心脏病,肝脏疾病,癌症等。如何维持谷胱甘肽含量稳定对于保护细胞免受外源药物损伤至关重要。
研究表明,维持谷胱甘肽动态平衡有两种方式,包括从其组成氨基酸开始的从头合成途径和在GPx参与下的GSH代偿性合成途径。其中从头合成途径是细胞维持GSH含量稳定的主要途径。GSH的从头合成途径主要依靠两个酶的催化,谷氨酰-L-半胱氨酸连接酶(glutamyl-L-cysteine ligase GCL)和GSH合成酶,GCL是GSH合成的限速酶,GCL酶活的调节可在基因转录水平、转录后水平、翻译后水平等环节。目前,提高GSH水平主要是通过提高GSH相关酶活性或诱导GCL表达来实现的。研究表明,N-乙酰半胱氨酸氨基化合物,N-乙酰半胱氨酸,腺苷蛋氨酸,五味子素B,白藜芦醇,L-2-羰基-4-噻唑啉-羧化物等化合物都是通过这种方式来增加GSH含量的。但是由于多种原因,这些化合物的使用常常受到限制,比如在体内,L-半胱氨酸可以发生自氧化,产生的不溶物具有神经毒性,NAC经口服或静脉注射后易被酶解等。
L-半胱氨酸前体分子被证明是一种提高体内GSH含量的关键化合物。本实验室以GlcNAc和L-半胱氨酸为底物合成了N-乙酰葡萄糖-噻唑啉-4-羧酸(N-acetyl-glucosamine-thiazolidine-4(R)-carboxylic acid, GlcNAcCys)。本课题组前期研究表明GlcNAcCys作为噻唑烷酸糖衍生物,具有重要的生物功能。GlcNAcCys能够作为L-半胱氨酸前体物,通过非酶开环水解反应释放L-半胱氨酸。GlcNAcCys具有较强的还原力和清除羟自由基、超氧阴离子自由基的能力,能够保护生物大分子(脱氧核糖,蛋白质的脂质)免受羟自由基的氧化损伤,提高APAP损伤小鼠肝脏内巯基含量。但是,GlcNAcCy提高巯基含量的机制尚不明确。
本研究以APAP诱导的小鼠肝损伤进一步研究了GlcNAcCys提高肝脏巯基含量的时间-效应关系,并以BSO耗竭肝脏GSH为模型,研究了GlcNAcCys提高GSH含量的机理。结果表明,GlcNAcCys能够提高肝脏总巯基含量以及GSH含量,其作用存在时间-效应关系。在BSO模型中,GlcNAcCys能提高肝脏抗氧化酶的活性,如GPx, GST的活性,诱导GCLmRNA的表达。诱导GCLmRNA表达可能是GlcNAcCys提高肝脏GSH含量,进而提高抗氧化酶活性,发挥肝保护作用的潜在机制。
The human body is inevitably exposed to different toxins and drugs. Metabolisms of these exogenous toxins and drugs in liver by phaseⅠand phaseⅡenzymes will result in excessive productin of free radicals and reactive intermediates. Reactive intermediates can conjugate with important biological macromolecules and result in body damage, such as oxidation, aging, and liver diseases. Under normal physiological conditions, the body has evolved mechanisms to counteract the damage caused by reactive metabolites to keep the reactive intermediates in a steady, balanced and low level. However, accumulation of excessive toxic products in the body will induce tissue dysfunction. Liver, which is the main organ responsible for drug accumulation, biotransformation, and metabolism, is the first subject to the most of the exogenous toxins and drugs and is more susceptible to different diseases compared with other organs. Exogenous-induced liver damage has become the leading cause of liver diseases and is receiving more attentions.
Glutathione (L-y-glutamyl-L-cysteinylglycine, GSH) is the ubiquitous low molecular weight cellular sulfhydryl and plays an important role in the body defense system. Glutathione exists in the reduced and the oxidized forms, which can be inter-converted by glutathione peroxidase (GPx) and glutathione reductase (GR). GSH also plays an important role in xenobiotic detoxification through direct sulfhydryl conjugation or indirectly as a co-factor of glutathione S-transferase (GST) and GPx. Excessive depletion of GSH has been shown to be related with apoptosis, redox imbalance, tissue dysfunctions, and diseases (such as cancer, liver disease, heart attack).Tissue GSH must be restored when it is depleted in order to protect cellular functions and integrity and to avoid further damages to other macromolecules.
Evidences show that various ways are involved for maintenance of GSH homeostasis, including de novo synthesis and GPx mediated regeneration of GSH. The de novo synthesis of glutathione from constituent amino acids is via a two-step pathway catalyzed by glutamylcysteine ligase (GCL) and GSH synthase, with the former being the rate limiting step. The steady level of GSH can be modulated at any point by regulating GCL transcription, expression, post-translational modification. Many strategies have been reported for pharmacologically maintaining or increasing tissue GSH levels. These strategies can be ascribed to inducing GSH-related enzymes and/or increasing L-cysteine availability. Some compounds N-acetylcysteine amide, N-acetylcysteine, S-adenosyl methionine, Schisandrin B, resveratrol, L-2-oxo-4-thiazolidine carboxylate have been reported to induced enzyme expression and/or increasing tissue or intracellular GSH contents. However these compounds are not always applicable. For examples, L-cysteine can auto-oxidize to insoluble L-cystine and is reported to have neuro-toxicity. N-acetyl-L-cysteine can be administered orally or intravenously but must be enzymatically deacetylated in cells.
We previously reported the preparation and characterization of a novel thiazolidine derivative N-acetyl-glucosamine-thiazolidine-4(R)-carboxylic acid (GlcNAcCys), which is cyclo-condensed from L-cysteine and N-acetyl-glucosamine. GlcNAc is the monosaccharide of chitin and shows many biological activities. GlcNAcCys can function as a L-cysteine prodrug to liberate free L-cysteine non-enzymatically in physiological pH in vitro and in vivo. With high reducing ability, GlcNAcCys can scavenge hydroxyl radicals and superoxide anion free radicals, protect biological macromolecules (deoxyribose, proteins and lipids) from free radical damage. In APAP induced liver damage, GlcNAcCys can increase liver sulfhydryl level. However, the mechanism underlying the increase in cellular sulfhydryl level by GlcNAcCys remains unclear.
In the present study, we used APAP induced liver damage to further investigate the effect-time relationship by GlcNAcCys and use L-buthionine-[S,R]-sulfoximine (BSO, a specific inhibitor of GCL) induced liver GSH depletion mice model to further investigate the mechanism of GSH content improvement by GlcNAcCys. Our results demonstrated that GlcNAcCys could increase liver T-SH and GSH concentrations; induce the activities of hepatic antioxidant enzymes (GPx, GST). BSO increased c-fos, c-jun transcription but had no effect on mRNA level of GCL. GlcNAcCys treatment could induce the mRNA level of GCL. The augmented activities of hepatic antioxidant enzymes and increased expression of GCL appeared to be the predominant mechanism underlying GlcNAcCys mediated liver protection against chemically induced damages.
细胞内的谷胱甘肽(L-γ-glutamyl-L-cysteinylglycine, GSH)是一种特殊的低分子量含巯基化合物,在机体防御系统中发挥着重要作用。谷胱甘肽分为氧化型和还原型两种形式,在谷胱甘肽过氧化物酶和谷胱甘肽还原酶的作用下,两种形式之间可以互相转化。谷胱甘肽既可以通过直接释放巯基基团起到解毒的作用,也可以作为谷胱甘肽过氧化物酶(glutathione peroxidase, GPx)和谷胱甘肽-S转移酶(glutathione S-transferase, GST)的底物来间接地发挥作用。细胞内谷胱甘肽的过度消耗会引起多种连锁反应,如细胞凋亡,氧化还原状态改变,组织功能异常,甚至会诱发多种疾病,如心脏病,肝脏疾病,癌症等。如何维持谷胱甘肽含量稳定对于保护细胞免受外源药物损伤至关重要。
研究表明,维持谷胱甘肽动态平衡有两种方式,包括从其组成氨基酸开始的从头合成途径和在GPx参与下的GSH代偿性合成途径。其中从头合成途径是细胞维持GSH含量稳定的主要途径。GSH的从头合成途径主要依靠两个酶的催化,谷氨酰-L-半胱氨酸连接酶(glutamyl-L-cysteine ligase GCL)和GSH合成酶,GCL是GSH合成的限速酶,GCL酶活的调节可在基因转录水平、转录后水平、翻译后水平等环节。目前,提高GSH水平主要是通过提高GSH相关酶活性或诱导GCL表达来实现的。研究表明,N-乙酰半胱氨酸氨基化合物,N-乙酰半胱氨酸,腺苷蛋氨酸,五味子素B,白藜芦醇,L-2-羰基-4-噻唑啉-羧化物等化合物都是通过这种方式来增加GSH含量的。但是由于多种原因,这些化合物的使用常常受到限制,比如在体内,L-半胱氨酸可以发生自氧化,产生的不溶物具有神经毒性,NAC经口服或静脉注射后易被酶解等。
L-半胱氨酸前体分子被证明是一种提高体内GSH含量的关键化合物。本实验室以GlcNAc和L-半胱氨酸为底物合成了N-乙酰葡萄糖-噻唑啉-4-羧酸(N-acetyl-glucosamine-thiazolidine-4(R)-carboxylic acid, GlcNAcCys)。本课题组前期研究表明GlcNAcCys作为噻唑烷酸糖衍生物,具有重要的生物功能。GlcNAcCys能够作为L-半胱氨酸前体物,通过非酶开环水解反应释放L-半胱氨酸。GlcNAcCys具有较强的还原力和清除羟自由基、超氧阴离子自由基的能力,能够保护生物大分子(脱氧核糖,蛋白质的脂质)免受羟自由基的氧化损伤,提高APAP损伤小鼠肝脏内巯基含量。但是,GlcNAcCy提高巯基含量的机制尚不明确。
本研究以APAP诱导的小鼠肝损伤进一步研究了GlcNAcCys提高肝脏巯基含量的时间-效应关系,并以BSO耗竭肝脏GSH为模型,研究了GlcNAcCys提高GSH含量的机理。结果表明,GlcNAcCys能够提高肝脏总巯基含量以及GSH含量,其作用存在时间-效应关系。在BSO模型中,GlcNAcCys能提高肝脏抗氧化酶的活性,如GPx, GST的活性,诱导GCLmRNA的表达。诱导GCLmRNA表达可能是GlcNAcCys提高肝脏GSH含量,进而提高抗氧化酶活性,发挥肝保护作用的潜在机制。
The human body is inevitably exposed to different toxins and drugs. Metabolisms of these exogenous toxins and drugs in liver by phaseⅠand phaseⅡenzymes will result in excessive productin of free radicals and reactive intermediates. Reactive intermediates can conjugate with important biological macromolecules and result in body damage, such as oxidation, aging, and liver diseases. Under normal physiological conditions, the body has evolved mechanisms to counteract the damage caused by reactive metabolites to keep the reactive intermediates in a steady, balanced and low level. However, accumulation of excessive toxic products in the body will induce tissue dysfunction. Liver, which is the main organ responsible for drug accumulation, biotransformation, and metabolism, is the first subject to the most of the exogenous toxins and drugs and is more susceptible to different diseases compared with other organs. Exogenous-induced liver damage has become the leading cause of liver diseases and is receiving more attentions.
Glutathione (L-y-glutamyl-L-cysteinylglycine, GSH) is the ubiquitous low molecular weight cellular sulfhydryl and plays an important role in the body defense system. Glutathione exists in the reduced and the oxidized forms, which can be inter-converted by glutathione peroxidase (GPx) and glutathione reductase (GR). GSH also plays an important role in xenobiotic detoxification through direct sulfhydryl conjugation or indirectly as a co-factor of glutathione S-transferase (GST) and GPx. Excessive depletion of GSH has been shown to be related with apoptosis, redox imbalance, tissue dysfunctions, and diseases (such as cancer, liver disease, heart attack).Tissue GSH must be restored when it is depleted in order to protect cellular functions and integrity and to avoid further damages to other macromolecules.
Evidences show that various ways are involved for maintenance of GSH homeostasis, including de novo synthesis and GPx mediated regeneration of GSH. The de novo synthesis of glutathione from constituent amino acids is via a two-step pathway catalyzed by glutamylcysteine ligase (GCL) and GSH synthase, with the former being the rate limiting step. The steady level of GSH can be modulated at any point by regulating GCL transcription, expression, post-translational modification. Many strategies have been reported for pharmacologically maintaining or increasing tissue GSH levels. These strategies can be ascribed to inducing GSH-related enzymes and/or increasing L-cysteine availability. Some compounds N-acetylcysteine amide, N-acetylcysteine, S-adenosyl methionine, Schisandrin B, resveratrol, L-2-oxo-4-thiazolidine carboxylate have been reported to induced enzyme expression and/or increasing tissue or intracellular GSH contents. However these compounds are not always applicable. For examples, L-cysteine can auto-oxidize to insoluble L-cystine and is reported to have neuro-toxicity. N-acetyl-L-cysteine can be administered orally or intravenously but must be enzymatically deacetylated in cells.
We previously reported the preparation and characterization of a novel thiazolidine derivative N-acetyl-glucosamine-thiazolidine-4(R)-carboxylic acid (GlcNAcCys), which is cyclo-condensed from L-cysteine and N-acetyl-glucosamine. GlcNAc is the monosaccharide of chitin and shows many biological activities. GlcNAcCys can function as a L-cysteine prodrug to liberate free L-cysteine non-enzymatically in physiological pH in vitro and in vivo. With high reducing ability, GlcNAcCys can scavenge hydroxyl radicals and superoxide anion free radicals, protect biological macromolecules (deoxyribose, proteins and lipids) from free radical damage. In APAP induced liver damage, GlcNAcCys can increase liver sulfhydryl level. However, the mechanism underlying the increase in cellular sulfhydryl level by GlcNAcCys remains unclear.
In the present study, we used APAP induced liver damage to further investigate the effect-time relationship by GlcNAcCys and use L-buthionine-[S,R]-sulfoximine (BSO, a specific inhibitor of GCL) induced liver GSH depletion mice model to further investigate the mechanism of GSH content improvement by GlcNAcCys. Our results demonstrated that GlcNAcCys could increase liver T-SH and GSH concentrations; induce the activities of hepatic antioxidant enzymes (GPx, GST). BSO increased c-fos, c-jun transcription but had no effect on mRNA level of GCL. GlcNAcCys treatment could induce the mRNA level of GCL. The augmented activities of hepatic antioxidant enzymes and increased expression of GCL appeared to be the predominant mechanism underlying GlcNAcCys mediated liver protection against chemically induced damages.
引文
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