Inhibition of hepatic microsomal enzymes by gossypol in the rat

The effect of the male contraceptive, gossypol, on rat liver microsomal enzymes has been studied in vitro and in vivo. In vitro, gossypol inhibited aminopyrine N-demethylase activity, the concentration causing 50% inhibition being approximately 0.03 mM; the inhibition was non-competitive. Also the metabolism of ethinylestradiol (a drug with a number of metabolic pathways) was inhibited with the main effect being reduced 2- and 16-hydroxylation. In vivo, gossypol, after 4 weeks of daily administration (30 mg/kg/day) caused a significant reduction in microsomal protein, cytochrome P450 and aminopyrine N-demethylase activity. However, despite reduced enzyme activity, the metabolism of tolbutamide (a drug with a single pathway of metabolism and hence a model substrate) was not impaired by either acute or chronic gossypol administration.