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The Utilization of N-Acetylcysteine and 2-Oxothiazolidine-4-Carboxylate by Rat Hepatocytes Is Limited by Their Rate of Uptake and Conversion to Cysteine^1,2,3,

Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853

N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (OTC) are converted enzymatically to cysteine and have been used to stimulate hepatic glutathione synthesis. Using hepatocytes isolated from male Sprague-Dawley rats and ³⁵S-labeled substrates, the uptake and metabolism of these cysteine precursors was measured and compared with those for cells provided with an equimolar amount of cysteine. Cysteine was utilized more rapidly than NAC or OTC for sulfate and taurine production and more rapidly than OTC for glutathione production. N-Acetyl-L-cysteine itself was taken up slowly by hepatocytes, but deacetylation of NAC to cysteine seemed to occur extracellularly. Utilization of OTC seemed to be limited by a low rate of uptake and slow intracellular conversion to cysteine. The rate of accumulation of [³⁵S]glutathione from OTC was low compared to that from other substrates, but glutathione production accounted for 78% of the measured OTC metabolism. Although the rate of accumulation of [³⁵S]glutathione was similar for hepatocytes incubated with [³⁵S]cysteine or [³⁵S]NAC, glutathione synthesis accounted for a higher percentage of NAC metabolism than of cysteine metabolism (62–81% vs. 46%). The apparent preferential distribution of OTC and NAC to glutathione vs. taurine and sulfate can be partly explained by a lower rate of substrate availability, but another unknown mechanism also appears to favor the conversion of NAC to glutathione.

KEY WORDS: • cysteine • hepatocytes • rats • N-acetylcysteine • thiazolidine

¹ Supported by the Cooperative State Research Service, U.S. Department of Agriculture under agreement no. 90-37200-5469 and by New York State Hatch Project 399-472.

² Presented in part at the 1992 FASEB Meetings, April 5–9, 1992, at Anaheim, CA [Banks, M. F. & Stipanuk, M. H. (1992) The utilization of N-acetylcysteine and 2-oxothiazolidine-4-carboxylate by rat hepatocytes is limited by their rate of transport and conversion to cysteine. FASEB J. 6: A1216 (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 1 July 1993. Revision accepted 18 October 1993.

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