Ribonucleotide reductase: an intracellular target for the male antifertility agent, gossypol

Gossypol is a yellow phenolic compound which reversibly inhibits spermatogenesis making it one of the few effective male antifertility drugs. The cytotoxic effects of gossypol have been associated with its ability to irreversibly inhibit DNA synthesis by a previously unknown mechanism. The results of this study indicate that gossypol is a potent inhibitor of ribonucleotide reductase the rate limiting enzyme activity in DNA synthesis. Furthermore, in agreement with these enzyme studies, DNA synthesis in a hydroxyurea resistant cell line with high levels of ribonucleotide reductase activity showed increased resistance to gossypol when compared to wild type cells with normal levels of reductase activity. Ribonucleotide reductase is the first specific site of action documented for gossypol which can explain its recently described antiproliferative, cell cycle and toxic effects.