Dysregulation of glutathione synthesis in liver disease
Shelly C. Lu
Abstract
Glutathione (GSH), a tripeptide that is present in all mammalian tissues, is especially highly concentrated in the liver. GSH synthesis occurs via two adenosine triphosphate (ATP)-requiring enzymatic steps: the first is rate-limiting, catalyzed by glutamate-cysteine ligase, generates γ-glutamylcysteine from glutamate and cysteine; the second is catalyzed by GSH synthetase, generates GSH from γ-glutamylcysteine and glycine. GSH defends against oxidative stress, participates in detoxification of xenobiotics, determines the redox status of the cell, and regulates vital processes such as growth and apoptosis. Hepatic GSH plays a central role in the interorgan GSH homeostasis because sinusoidal efflux of hepatic GSH determines plasma GSH level. In liver diseases GSH homeostasis is perturbed by multiple mechanisms. Hepatic GSH biosynthesis is impaired in cholestatic liver injury, endotoxemia, and fibrotic injury largely because the expression of the GSH synthetic enzymes falls. Lower hepatic GSH level further exacerbates and perpetuates ongoing liver injury. However, in hepatocellular carcinoma GSH synthetic enzymes are upregulated and this may play a role in chemoresistance. This review focuses on the current understanding of hepatic GSH synthesis in health and disease.