Protection of rat myocardial phospholipid against peroxidative injury through superoxide-(xanthine oxidase)-dependent, iron-promoted Fenton chemistry by the male contraceptive gossypol.
Metal-promoted oxygen free-radical chemistry is a cause of tissue damage in many disease states, such as myocardial ischemia. The effect of gossypol, a polyphenolic plant pigment and male contraceptive, on the peroxidation of myocardial membrane phospholipid was studied and quantitatively characterized. As a result of exposure to xanthine oxidase (superoxide)-dependent, iron-promoted Fenton chemistry, cardiac phospholipid was readily peroxidized with defined kinetics. The peroxidation could be blocked by substances which interdict at specific points in the Fenton chemistry: superoxide dismutase, alpha-tocopherol, the iron chelator desferrioxamine, and the xanthine oxidase substrate-analogs allopurinol and oxypurinol. The oxidative-injury system displayed a characteristic antiperoxidant response to each type of inhibitor. Gossypol, at low micromolar concentrations, profoundly altered the rate and extent of myocardial phospholipid peroxidation. Gossypol was ineffective as a xanthine oxidase inhibitor and as a superoxide scavenger at concentrations that abolished myocardial lipid peroxidation. Since metal chelation was an effective means of preventing lipid peroxidation in this system only when the iron therein was completely chelated, the low anti-peroxidant IC50 for gossypol, 1.1. microM, relative to the concentration of iron (100 microM) did not support a functionally significant antiperoxidant role for gossypol as an iron chelator. Rather, it appears that, at low micromolar gossypol concentrations which approximate the peak plasma concentrations in humans, the antiperoxidant effects of gossypol against superoxide-mediated, iron-promoted lipid damage rest with the ability of gossypol to intercept lipid radical intermediates as a "chain-breaking" aromatic phenol.
Janero
D R
DR
Department of Pharmacology and Chemotherapy, Roche Research Center, Hoffmann-La Roche, Inc., Nutley, NJ 07110.
Burghardt
B
B
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006072:Gossypol / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008054:Lipid Peroxides / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D010117:Oxypurinol / Q000494:pharmacology; D051381:Rats; D013481:Superoxides; D014969:Xanthine Oxidase / Q000378:metabolism*
D008054:Lipid Peroxides; D013481:Superoxides; D000493:Allopurinol; D014969:Xanthine Oxidase; D010117:Oxypurinol; D006072:Gossypol