Role of Glutathione in Drug-Induced Liver Injury
Glutathione (GSH) serves as the primary hepatic defense mechanism against drug-induced liver injury by directly detoxifying reactive drug metabolites through conjugation reactions catalyzed by glutathione S-transferase (GST), and GSH depletion is the critical pathophysiologic event that precipitates hepatocyte necrosis in most cases of direct DILI.
Mechanism of Glutathione Protection in DILI
Direct Detoxification Pathway
- GSH conjugates with reactive metabolites to facilitate their urinary excretion, preventing these toxic intermediates from binding to hepatocellular proteins and causing cell death 1
- When acetaminophen (the prototypical DILI agent) is taken in excess, it produces N-acetyl-p-benzoquinone imine (NAPQI), which normally binds to GSH for detoxification 1
- Once hepatic GSH stores are depleted below critical thresholds, NAPQI binds directly to biomacromolecules in the liver causing hepatocyte injury 1
GSH Synthesis as a Protective Factor
- Glutamate-cysteine ligase (GCL) performs the rate-limiting first step in GSH synthesis, and overexpression of this enzyme confers significant resistance to acetaminophen-induced liver injury in male mice 2
- Male transgenic mice overexpressing GCL exhibited marked resistance to acetaminophen hepatotoxicity compared to controls, demonstrating that GCL activity is a critical determinant of susceptibility to DILI 2
- Variation in human GCL activity may explain individual differences in susceptibility to acetaminophen-induced liver injury 2
Clinical Implications of GSH Depletion
Diagnostic Utility
- When liver is seriously damaged, both GST and GSH are released from hepatocyte cytosol into plasma, causing lower GST activity in remaining liver tissue 3
- Monitoring GST activity levels in liver tissue represents a potential diagnostic strategy for DILI, as decreased hepatic GST activity correlates with severity of liver injury 3
- Two-photon fluorescent probes for GST detection have been successfully applied in imaging DILI samples, demonstrating practical application as a potential diagnostic method 3
Predictive Animal Models
- Selenium and GSH-depleted rats represent the most sensitive animal model for predicting human DILI, as rodents normally possess superior hepatoprotective capacity compared to humans 4
- Se/GSH-depleted rats show decreased glutathione peroxidase-1 expression and GSH levels with increased lipid peroxidation (malondialdehyde) in liver 4
- Flutamide, which causes DILI in humans but not in intact rats, produces hepatotoxicity in Se/GSH-depleted rats at 150 mg/kg for 5 days, validating this model's predictive value 4
Therapeutic Implications
Restoration of GSH Pathways
- Activation of the Nrf2 signaling pathway and regulation of GSH synthesis, coupling, and excretion are mechanisms by which certain natural products (such as ginsenoside Rg1) treat acetaminophen-induced acute liver injury 1
- Anti-miR-873-5p treatment restores glycine N-methyltransferase (GNMT) and methionine cycle activity, which enhances GSH synthesis and reduces mitochondrial dysfunction in DILI 5
- Restoration of the methionine cycle increases S-adenosylmethionine (AdoMet) levels, which are typically decreased during DILI, preventing mitochondrial dysfunction while activating hepatocyte proliferative response 5
Critical Timing Considerations
- N-acetyl cysteine (NAC), which replenishes GSH stores, must be administered within 8 hours of acetaminophen overdose to be effective, as late-stage DILI currently lacks effective treatment options 5
- This narrow therapeutic window underscores the importance of early GSH repletion before irreversible hepatocyte injury occurs 5
Key Clinical Pitfalls
- Do not assume that normal baseline liver function tests exclude vulnerability to DILI in patients with subclinical GSH depletion from malnutrition, chronic alcohol use, or selenium deficiency 4
- Recognize that the superior antioxidant capacity in standard rodent models may fail to predict human DILI risk, as humans have relatively lower hepatic GSH reserves 4
- Individual variation in GCL activity means some patients are inherently more susceptible to GSH depletion and subsequent DILI, even at standard drug doses 2