Subcellular site of antispermatogenic effect of gossypol and its possible molecular mechanism of action.
This paper reports the results of gossypol effects on the testicular mitochondrial ultrastructures and functions. A hypothesis of mechanism of gossypol action based on our experimental data was postulated. Electron microscopic observations confirmed further our previous studies that the mitochondria of the target germ cells were the most sensitive and the most severely damaged among cellular organelles in response to gossypol. The damages included the swelling, vacuolation, crista depletion, lysis, granular accumulation in matrix and the process of intact mitochondria disintegration. The activity of the mitochondrial marker enzyme, the LDH-X of human spermatozoa, was markedly decreased or suppressed completely after gossypol treatment. The functions of isolated testicular mitochondria determined by Warburg manometric and oxygen electrode polarographic methods indicated that gossypol stimulated respiration but inhibited slightly the oxidative phosphorylation at low concentrations (20-40 microM) in vitro. With the increase in concentration of gossypol, the mitochondrial respiration and phosphorylation decreased obviously, they were completely inhibited at a concentration of 80 microM for oxidative phosphorylation and at about 300 microM for respiration. The degree of uncoupling of phosphorylation appears to be dose-dependent. Similar results were obtained for the testicular mitochondria isolated from rats that had been administered per os gossypol previously (6 mg, 10 mg and 15 mg/day X 21 respectively), in which the P/0 ratio decreased significantly (P less than 0.001) as compared with that of the control group. The distribution of 14C-gossypol in mitochondrial was found to be 2-3 times higher than that in other subcellular fractions. Similar pattern of distribution was shown in double labeling experiments with 14C-gossypol and 3H-ouabain.
D000818:Animals; D006072:Gossypol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D010085:Oxidative Phosphorylation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000648:ultrastructure; D013737:Testis / Q000187:drug effects* / Q000378:metabolism; D014018:Tissue Distribution
D007770:L-Lactate Dehydrogenase; D006072:Gossypol