ATTENUATION OF ACETAMINOPHEN HEPATOTOXICITY IN MICE AS EVIDENCE FOR THE BIOAVAILABILITY OF THE CYSTEINE IN D-GLUCOSE-L-CYSTEINE IN-VIVO

A substantial fraction of the cysteine added to total parenteral nutri tion (TPN) solutions is converted to the corresponding thiazolidine de rivative, while in solution with relatively large concentrations of gl ucose typical of TPN (700 mM and higher). It was recently reported (Ro berts et al. (1987) J. Med. Chem. 30, 1891-1896) that this thiazolidin e, D-glucose-L-cysteine (DGC), offered no significant protection again st the hepatic injury caused by 5 mmol/kg of acetaminophen in mice, su ggesting that the cysteine present as DGC is poorly bioavailable in vi vo. In the present study, fasted male ICR mice given 1.6 or 2.6 mmol/k g of acetaminophen sustained hepatic injury, estimated by elevations i n plasma alanine aminotransferase (ALT) activities. Administration of 2.5 mmol/kg of N-acetylcysteine (NAC) 1 h before acetaminophen given i .p. prevented the rise in plasma ALT activities, apparently through su pport of glutathione (GSH) synthesis. Administration of 2.5 mmol/kg of DGC prior to acetaminophen resulted in slightly lower mean plasma ALT activities than were observed in animals given saline before acetamin ophen, but the effect was not statistically significant. When DGC was given 1 h before p.o. administration of 1.6 or 2.6 mmol/kg of acetamin ophen, the protective effects of DGC were statistically significant (P < 0.01, 0.025, respectively), although NAC afforded significantly gre ater protection than did DGC at the higher dose of acetaminophen. Give n 4 h before acetaminophen, DGC attenuated acetaminophen-induced incre ases in plasma ALT activities significantly, whereas NAC was without e ffect. These results indicate that the cysteine in DGC is at least par tially bioavailable in vivo and, further, that DGC may function as a s low release formulation of cysteine.