Gossypol is a polyphenolic compound derived from the cotton plant which exerts antispermatogenic effects in man and experimental animals. It holds considerable promise as an oral male contraceptive in man yet little is known about its mechanism of action on the testis at the molecular level. The hypothesis to be tested in this proposal is that gossypol inhibits spermatogenesis by preferentially interacting with the enzyme lactic dehydrogenase-X (LDH-X) in specific spermatogenic cells, ie, spermatids, and that the consequence of this inhibition is impairment of energy production and eventual cell death. The study will be carried out with a nonhuman primate model, the cynomolgus monkey (M. fascicularis) in which the antispermatogenic and clinical effects of gossypol are known. Our approach will be (1) To demonstrate more conclusively, using LDH isozymes purified from monkey sperm, heart, and liver that gossypol preferentially inhibits LDH-X and then to determine the mechanism of this inhibition. (2) We will then determine if energy metabolism is inhibited by gossypol in vitro in isolated monkey pachytene speratocytes and spermatids in a manner which correlates with the relative amount of cellular LDH-X. (3) Finally, we will administer gossypol orally to cynomolgus monkeys and then determine, after isolation of spermatocytes and spermatids and incubation in vitro, whether the biochemical consequence of oral administration is the inhibition of LDH-X in spermatids in the intact animal.
| Stephens, D T; Whaley, K J; Klimkow, N M et al. (1986) Kinetic characterization of the inhibition of purified cynomolgus monkey lactate dehydrogenase isozymes by gossypol. J Androl 7:367-77 |
| Whaley, K J; Stephens, D T; Klimkow, N M et al. (1986) Monkey lactate dehydrogenase-C4 as a model for the interaction of enzymes with gossypol. Contraception 33:605-16 |
