Studies of the mechanism of action of gossypol as a male antifertility agent.
Gossypol administered orally to male rats at a daily dose of 20 mg/kg body weight for 62 days caused infertility. There were changes in the epididymal epithelium and the sperm were severely damaged and immotile. The sperm head was often detached; other defects were abnormal mitochondria, absence of plasma membranes and axonemal and accessory fibres and a lower oxygen uptake. To study the effect of gossypol on the motor apparatus of sperm, ram sperm were demembranated with the detergent, Triton-X-100. Such sperm models can normally be reactivated with ATP but gossypol (2.5-12.5 microM) decreased reactivation and must have a direct effect on the axoneme. Gossypol also inhibited ram sperm adenyl cyclase which is essential for maintaining high levels of cAMP in sperm and, in turn, motility. Ram sperm adenyl cyclase required Mn2+ for activity and high Mn2+ concentrations protected the enzyme from gossypol inhibition. Electron spin resonance studies proved that gossypol chelated Mn2+ with the formation of a 2:1 complex.
White
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Department of Veterinary Physiology, University of Sydney, N.S.W., Australia.
Vishwanath
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Swan
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Brown-Woodman
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D000255:Adenosine Triphosphate / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D005298:Fertility / Q000187:drug effects*; D006072:Gossypol / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008345:Manganese / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012756:Sheep; D013081:Sperm Motility / Q000187:drug effects; D013094:Spermatozoa / Q000187:drug effects / Q000201:enzymology
D008345:Manganese; D000255:Adenosine Triphosphate; D000262:Adenylyl Cyclases; D006072:Gossypol