Effects of chronic ethanol feeding on rat hepatocytic glutathione. Relationship of cytosolic glutathione to efflux and mitochondrial sequestration

J C Fernandez-Checa ¹, M Ookhtens , N Kaplowitz

⁰Liver Research Laboratory, Wadsworth Veterans Administration Medical Center, Los Angeles, California 90073.

The Journal of Clinical Investigation +

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April 1, 1989

View abstract on PubMed

Summary

Chronic ethanol consumption impairs hepatic glutathione (GSH) regulation, decreasing mitochondrial GSH levels and altering efflux kinetics. This affects cellular defense mechanisms in the liver.

Area Of Science

Hepatology
Biochemistry
Cellular Biology

Background

Chronic ethanol intake alters hepatic glutathione (GSH) metabolism.
Previous studies indicated increased GSH efflux, but biliary efflux remained unchanged in vivo.
Cellular GSH concentration-dependent efflux requires further kinetic investigation.

Purpose Of The Study

To investigate the kinetic parameters of cellular GSH efflux in chronic ethanol-fed rats.
To examine the relationship between cytosolic GSH and GSH efflux rate.
To assess mitochondrial GSH levels and resynthesis capacity in ethanol-exposed liver cells.

Main Methods

Utilized chronic ethanol-fed and pair-fed rat models.
Measured in vitro hepatic cellular GSH efflux using kinetic modeling (Hill equation).
Quantified cytosolic and mitochondrial GSH levels and assessed GSH resynthesis rates.

Main Results

Ethanol-fed cells exhibited a decreased Km for GSH efflux, indicating altered affinity, while Vmax remained similar.
Mitochondrial GSH levels were significantly reduced in ethanol-fed cells across all cytosolic GSH concentrations.
Impaired reaccumulation of mitochondrial GSH was observed in ethanol-fed cells, with the earliest change being a 50% decrease at 2 weeks.

Conclusions

Chronic ethanol feeding alters hepatic GSH efflux kinetics and significantly depletes mitochondrial GSH.
Impaired mitochondrial GSH repletion suggests a critical disruption in cellular redox homeostasis.
These findings highlight a novel mechanism of ethanol-induced liver injury related to GSH regulation.

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