Metal chelators reverse the action of hydrogen peroxide in rat luteal cells

In rat luteal cells hydrogen peroxide (H₂O₂) interferes with the functional coupling of the luteinizing hormone (LH) receptor and blocks cAMP-dependent progesterone production. To test if this action of H₂O₂ is dependent on the generation of hydroxyl radicals, the effects of metal chelators and hydroxyl radical scavengers were evaluated. The heavy metal chelator O-phenanthroline prevented H₂O₂ inhibition of LH-sensitive cAMP and progesterone accumulation and depletion of ATP. Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) partially reversed inhibition of cAMP accumulation by H₂O₂ and completely prevented H₂O₂-induced ATP depletion, but had no effect on H₂O₂ inhibition of progesterone synthesis. Three other heavy metal chelators, deferoxamine, bathocuproinedisulfonic acid (BA) and penicillamine, as well as hydroxyl radical scavengers ethanol, thiourea and N-(2-mercaptopropiony1)glycine (MPG), had no effect on the luteolytic actions of H₂O₂. Differential effects of the chelators were probably due to differences in their cell permeability and subcellular compartmentalization. We conclude that metal chelators block the luteolytic actions of H₂O₂ by a mechanism probably linked to inhibition of hydroxyl radical generation.