[33] Thiyl free radical metabolites of thiol drugs, glutathione, and proteins

This chapter discusses the thiyl free radical metabolites of thiol drugs, glutathione (GSH), and proteins. The oxidation of the thiol group of cysteine is involved in several functions of GSH and proteins. The one-electron oxidation of the thiol group of cysteine catalyzed by a metal ion or a radiolytic process results in the formation of a thiyl radical. The thiyl radical can undergo dimerization to the corresponding disulfide or react with oxygen or hydrogen peroxide (H2O2) to produce the oxygen-containing products. The thiyl radical and products are responsible for the bactericidal effect of cysteine 3 and the radioprotection afforded by GSH and related thiol compounds. The glutathionyl radical generated from glutathione thionitrite has been shown to cause mutagenicity in Salmonella typhimurium TA100. The mechanism by which the thiyl radical of cysteine or GSH may be formed in vivo is by reaction with a peroxidase enzyme. This has been demonstrated for cysteine and GSH using isolated enzymes such as horseradish peroxidase (HRP), lactoperoxidase, and prostaglandin H synthase. Thiyl free radical metabolites formed in vivo, or in the presence of isolated enzymes, can be detected by electron spin resonance (ESR) spectroscopy using a spin trap. Spin trapping is a technique where a diamagnetic molecule (the spin trap) reacts with a free radical to produce a more stable radical (or spin adduct) that can be detected by ESR spectroscopy.