Probing into the mechanism of action, metabolism and toxicity of gossypol by studying its (+)- and (-)-stereoisomers.
The chemistry of gossypol is very relevant to its unique actions. The two aldehyde groups can easily bind to proteins via aldehyde-amino group linkage. Gossypolone, the in vivo oxidation product of gossypol, may form a redox system with its corresponding hemiquinone, leading to free radical generation. There are marked differences in the disposition and metabolism between (+)- and (-)-gossypol. The elimination half life of (+)-gossypol was much longer than that of (-)-gossypol. The higher rate of elimination of (-)-gossypol may be due to its lower rate of binding to tissue proteins, since the Vd of (-)-gossypol was much smaller than that of the (+)-isomer. A single intratesticular injection of 200 micrograms of (-)-gossypol caused a 70.4% decrease of the sperm count along with marked atrophy of the testes. However, neither a significant decrease in sperm count nor atrophy of the testes was observed after a similar injection of (+)-gossypol, suggesting that there is a strict stereochemical requirement for the interaction between gossypol and the testicular target molecules. Racemic gossypol stimulated superoxide free-radical formation when incubated with either rat liver or kidney microsomes, but not with those of the heart or testes. Pretreatment with phenobarbital potentiated this effect in liver microsomes, while incubation with metyrapone decreased in renal microsomes. Both (+)- and (-)-gossypol exhibited similar potencies in renal or hepatic microsomes in vitro. At 100 mg/kg, both (+)- and (-)-gossypol were able to cause increases in SGPT in rats 12 and 24 h following the administration. The equipotency between the two isomers in causing toxic effects to some of the somatic tissues and the stereo-selectivity of (-)-gossypol to induce antispermatogenic effects indicate that gossypol may actually exhibit two categories of cytotoxic effects to different organs and tissues. This suggests that one may be able to eliminate one effect while keeping the other.
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D000818:Animals; D006072:Gossypol / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D051381:Rats; D013237:Stereoisomerism
D006072:Gossypol