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Regulation of Hepatocyte Glutathione by Amino Acid Precursors and cAMP in Protein-Energy Malnourished Rats^1,2,3,

Department of Nutritional Science, University of Guelph, Guelph, Ontario, Canada ON N1G 2W1

Hepatic glutathione concentration is decreased in protein-energy malnutrition. Malnourished rats are able to replenish hepatic glutathione after oral supplementation with L-2-oxothiazolidine-4-carboxylate, a cysteine pro-drug, to levels that are higher than in control rats. These results suggest that, even if a normal amount of amino acids for glutathione synthesis is provided, homeostatic control of glutathione concentration after protein-energy malnutrition is abnormal. The rate limiting enzyme for glutathione synthesis, -glutamylcysteine synthetase, is subject to both short and long term hormonal control. Therefore, we used hepatocytes isolated from weanling rats fed a very low protein diet (0.5 g protein/100 g diet) or a diet adequate in protein for 2 wk to investigate whether a loss of hormonal control could contribute to abnormal regulation of hepatic glutathione. Glutathione concentration in hepatocytes isolated from protein-energy malnourished rats was 82% lower than in controls. In vitro supplementation of isolated hepatocytes with oxothiazolidine-4-carboxylate or methionine increased glutathione concentration in hepatocytes from malnourished rats to concentrations equivalent to control cells. However, when hepatocytes were incubated with cysteine, total glutathione in malnourished rats exceeded that of controls. Treatment of cells from control rats with 50 nmol/L glucagon or 1 mmol/L db-cAMP decreased glutathione concentration by 25–43%. In contrast, the glutathione concentration in hepatocytes of rats fed the low protein diet did not respond to treatment with glucagon or db-cAMP. These data indicate that glutathione synthesis is insensitive to regulation by cAMP in rats with protein-energy malnutrition. This loss of responsiveness to hormonal control may contribute to the abnormal homeostatic regulation of hepatic glutathione observed in protein-energy malnutrition.

KEY WORDS: • rats • glutathione • cAMP • malnutrition • hepatocytes

¹ Supported in part by grants from the ILSI North America to L. E. Nagy and NSERC to T. M. Bray.

² Presented in part at the Annual Meeting of the Canadian Federation of Biological Sciences, June 17–19, 1993, Windsor, ON [Goss, P. M., Bray, T. M. & Nagy, L. E. (1993) Hepatocyte glutathione content in protein-energy malnutrition: regulation by substrates and cAMP. Can. Fed. Biol. Sci. 36: 63(abs.)].

³ The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC section 1734 solely to indicate this fact.

⁴ To whom correspondence should be addressed.

Manuscript received 19 August 1993. Revision accepted 22 October 1993.