Biodistribution of [³⁵S]-cysteine and cysteine prodrugs: Potential impact on chemoprotection strategies

Thiazolidine prodrugs of L-cysteine constructed with aldose monosaccharides as the carbonyl donor offer powerful protection against acetaminophen (APAP)-induced hepatotoxicity, but require large doses to be effective. Using disaccharides in prodrug synthesis produces a thiazolidine ring form with a cyclic sugar moiety present. This structural motif may allow the delivery of the prodrug to specific carbohydrate receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, thus reducing the required dose of prodrug and enhancing the effectiveness of cytoprotection. The biodistribution of [³⁵S]-labeled prodrugs was investigated in Swiss-Webster mice, both in the presence and absence of APAP, and compared to labeled L-cysteine itself. Accumulation of radioactivity in liver appeared to be stimulated by the presence of APAP in some cases, but organ levels after prodrug administration were much lower than after the administration of L-cysteine itself. These studies identified differences in the biodistribution of L-cysteine prodrugs of different structural types, as well as effects of the hepatotoxin on localization, but the occurrence of targeted delivery to hepatocytes remains speculative.