The pharmacology and toxicology of polyphenolic-glutathione conjugates

Polyphenolic-glutathione (GSH) conjugates and their metabolites retain the electrophilic and redox properties of the parent polyphenol. Indeed, the reactivity of the thioether metabolites frequently exceeds that of the parent polyphenol. Although the active transport of polyphenolic-GSH conjugates out of the cell in which they are formed will limit their potential toxicity to those cells, once within the circulation they can be transported to tissues that are capable of accumulating these metabolites. There are interesting physiological similarities between the organs that are known to be susceptible to polyphenolic-GSH conjugate-mediated toxicity. In addition, the frequent localization of gamma-glutamyl transpeptidase to cells separating the circulation from a second fluid-filled compartment coincides with tissues that are susceptible either to polyphenolic-GSH conjugate-induced toxicity or to quinone and reactive oxygen species-induced toxicity. Polyphenolic-GSH conjugates therefore contribute to the nephrotoxicity, nephrocarcinogenicity, and neurotoxicity of a variety of polyphenols.