THE UTILIZATION OF N-ACETYLCYSTEINE AND 2-OXOTHIAZOLIDINE-4-CARBOXYLATE BY RAT HEPATOCYTES IS LIMITED BY THEIR RATE OF UPTAKE AND CONVERSION TO CYSTEINE

N-Acetyl-L-cysteine (NAC) and L-2-oxothiazolidine-4-carboxylate (OTC) are converted enzymatically to cysteine and have been used to stimulat e hepatic glutathione synthesis. Using hepatocytes isolated from male Sprague-Dawley rats and S-35-labeled substrates, the uptake and metabo lism 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 product ion and more rapidly than OTC for glutathione production. N-Acetyl-L-c ysteine itself was taken up slowly by hepatocytes, but deacetylation o f NAC to cysteine seemed to occur extracellularly. Utilization of OTC seemed to be limited by a low rate of uptake and slow intracellular co nversion to cysteine. The rate of accumulation of [S-35]glutathione fr om 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 [S-35]glutathione was similar for hepatoc ytes incubated with [S-35]cysteine or [S-35]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 expl ained by a lower rate of substrate availability, but another unknown m echanism also appears to favor the conversion of NAC to glutathione.