N-Acetylcysteine Stereoisomers as in vivo Probes of the Role of Glutathione in Drug Detoxification

It is well established throughout this and earlier volumes devoted to glutathione that this abundant cellular thiol sustains a wide range of protective and maintenance processes. Protective functions include the conjugation of electrophilic toxicants and the reduction of damaging oxidants and free radicals. This chapter describes how stereoisomers of N-acetylcysteine can be used to gain unique insights into detoxification reactions governed by glutathione, including (1) molecular details of mechanisms of glutathione action, (2) the role played by glutathione when N-acetylcysteine rescues patients from toxic and potentially lethal overdoses, and (3) the importance of glutathione-like reactions that could contribute to the clinical efficacy of the antidote. Although this chapter emphasizes the use of stereoisomers to understand the prevention of acetaminophen hepatotoxicity, the stereoisomer approach should prove useful in evaluating other glutathione-mediated detoxification reactions and specific mechanisms of glutathione action.