THIOL-MEDIATED NTA-FE(III) REDUCTION AND LIPID-PEROXIDATION

The nephrotoxicity of nitrilotriacetate chelated Fe(m) (NTA-Fe(III)) h as been linked to the metabolism of glutathione (GSH) by gamma-glutamy l transpeptidase and a dipeptidase. The products of these enzymes are cysteinyl-glycine (cys-gly) and cysteine (cys), which are proposed to be the reductants of NTA-Fe(III) to cause oxidative damage to various biomolecules. The ability of cys-gly and cys to cause in vitro NTA-Fe( III)-dependent lipid peroxidation correlated directly with their abili ty to reduce NTA-Fe(III). GSH reduced iron at a much slower rate and d id not stimulate lipid peroxidation. It has been proposed that GSH, cy s-gly and cys reduce iron at different rates because their thiols have different pK(a)s. However, increasing the amount of GS(-), by raising the pH, did not cause a corresponding increase in the rate of iron re duction. The monomethyl ester of GSH reduced NTA-Fe(III) at the same r ate as GSH, but the dimethyl ester of GSH reduced NTA-Fe(III) approxim ately 30 times faster. From this we conclude that GSH does not reduce NTA-Fe(III) at the same rate as cys-gly and cys because of the ligandi ng between GSH and the iron. (C) 1994 Academic Press, Inc.