谷氨素-1通过降低其有毒代谢物减轻了乙氨基引起的肝损伤
Ying Xu1, Yan Xia1, Qinhui Liu1
1Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Journal of pharmaceutical analysis
|January 15, 2024
概括
谷氨素-1 (Glrx1) 通过减少有毒代谢物形成和氧化应激,保护免受乙胺过量诱导的肝损伤. 升高 Glrx1 可能为急性肝衰竭提供治疗策略.
科学领域:
- 生物化学 生物化学
- 毒理学 毒理学 毒理学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 乙氨基 (APAP) 过量服用会通过过度的N-乙-p-基胺 (NAPQI) 形成引起急性肝衰竭 (ALF),导致氧化应激和肝细胞亡.
- S-谷氨基化是一种关键的翻译后修改,与APAP肝毒性有关,Glutaredoxin-1 (Glrx1) 通过脱谷氨基化对其逆转至关重要.
研究的目的:
- 研究Glrx1在APAP诱导的ALF病变发生中的作用.
- 阐明Glrx1影响APAP代谢和氧化应激的机制.
主要方法:
- 使用了 Glrx1 淘汰 (Glrx1-/-) 和肝部特异性 Glrx1 过度表达 (AAV8-Glrx1) 的小鼠,这些小鼠接受了 APAP 诱导的 ALF.
- 在 APAP 暴露之前,作为潜在的 Glrx1 诱导剂,为评估保护作用而使用Pirfenidone (PFD).
- 量化肝脏S-谷氨基化,Glrx1水平,氧化应激标志物和APAP有毒代谢物形成.
主要成果:
- 由于APAP的毒性,导致肝脏蛋白S-氨基化 (PSSG) 的增加,并降低了Glrx1水平.
- Glrx1-/-小鼠对APAP表现出高度敏感,其特征是氧化应激和有毒代谢物增加,与增加PSSG和S-glutathionylation的细胞染色体P450 3a11 (Cyp3a11) 相关.
- AAV8-Glrx1小鼠和PFD治疗的小鼠对APAP诱导的ALF具有保护性,S-氨基化减少,Cyp3a11活性降低,有毒代谢物减少,氧化应激减弱.
结论:
- Glrx1通过调节PSSG和影响Cyp3a11活动,在减轻APAP诱导的肝损伤方面发挥着关键的保护作用.
- 调节Glrx1表达是一种有前途的治疗途径,用于管理APAP诱导的肝毒性和ALF.
相关概念视频
Phase II Reactions: Glutathione Conjugation and Mercapturic Acid Formation
212
Glutathione, a tripeptide made up of glutamate, cysteine, and glycine, is a critical player in the detoxification of drugs and xenobiotics via a process known as glutathione conjugation or mercapturic acid formation. This phase II biotransformation reaction involves the covalent binding of glutathione to a drug or its metabolite, enhancing the compound's water solubility and enabling its excretion.
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
Several distinctive characteristics distinguish glutathione conjugation from other phase II...
212
Phase II Reactions: Acetylation Reactions
229
Acetylation, a phase II biotransformation reaction, introduces an acetyl group to drugs or their metabolites. Acetyltransferase enzymes facilitate this reaction, which resembles α-amino acid conjugation due to the addition of a functional group to the drug molecule.
The substrates for acetylation are typically drugs or their metabolites with an amino, sulfonamide, or hydrazine functional group. Acetylation can occur at several points in the drug molecule, including primary, secondary, and...
The substrates for acetylation are typically drugs or their metabolites with an amino, sulfonamide, or hydrazine functional group. Acetylation can occur at several points in the drug molecule, including primary, secondary, and...
229
Enhanced Elimination of Poison
514
Poison can be effectively removed from the gastrointestinal (GI) tract through various decontamination procedures.
Antidotes serve a crucial role in counteracting the effects of poison by inhibiting enzymes responsible for producing harmful drug metabolites. In some cases, these toxic metabolites can be neutralized by endogenous cosubstrates, which are maintained at specific concentrations to prevent interaction with cellular macromolecules and subsequent cell death.
Renal excretion is the...
Antidotes serve a crucial role in counteracting the effects of poison by inhibiting enzymes responsible for producing harmful drug metabolites. In some cases, these toxic metabolites can be neutralized by endogenous cosubstrates, which are maintained at specific concentrations to prevent interaction with cellular macromolecules and subsequent cell death.
Renal excretion is the...
514
Acetals and Thioacetals as Protecting Groups for Aldehydes and Ketones
4.2K
Acetals are formed by reacting two equivalents of alcohol with carbonyl compounds like aldehydes or ketones. Acetals are unaffected by bases, nucleophiles, oxidizing agents, and reducing agents. They serve as protecting groups for aldehydes and ketones. Acetals can be easily formed and also easily removed via mild acid hydrolysis.
In the presence of multiple functional groups, when selective reduction of one group over the other is desired, groups like aldehydes and ketones that form acetals...
In the presence of multiple functional groups, when selective reduction of one group over the other is desired, groups like aldehydes and ketones that form acetals...
4.2K
Phase I Reactions: Oxidation of Aliphatic and Aromatic Carbon-Containing Systems
202
Phase I biotransformation reactions are integral to drug metabolism, predominantly involving oxidative, reductive, and hydrolytic transformations. Chief among these are oxidative reactions, which enhance the hydrophilicity of xenobiotics and introduce polar functional groups to facilitate their elimination from the body.
Oxidation reactions are fundamental in aromatic carbon-containing systems. An example is the hydroxylation of phenobarbital, a process that transforms it into...
Oxidation reactions are fundamental in aromatic carbon-containing systems. An example is the hydroxylation of phenobarbital, a process that transforms it into...
202
Phase II Reactions: Glucuronidation
437
Glucuronidation, a pivotal phase II biotransformation process, involves the coupling of glucuronic acid to a drug or xenobiotic. Given its widespread occurrence and critical role in drug metabolism, it's considered the most crucial phase II reaction. It enhances the water solubility of substances, aiding their expulsion from the body. The driving force behind these reactions is a group of enzymes known as UDP-glucuronosyltransferases (UGTs). UGTs facilitate the transfer of a glucuronic acid...
437


