Primary mitochondrial activity of gossypol in yeast and mammalian cells

Gossypol showed primary antimitochondrial activity in yeast cells in that the drug (1) inhibited growth of cells utilizing mitochondrial substrates as carbon and energy sources, and (2) selectively inhibited mitochondrial protein synthesis. Primary antimitochondrial activity was demonstrated in guinea-pig keratinocytes (GPK) by early arrest of growth and loss of viability in medium with glutamine (a mitochondrial substrate) as carbon and energy source compared with cells utilizing glucose. Gossypol depressed oxygen uptake directly in respiring cells. Gossypol interacted with the known antimitochondrial agents ethidium bromide and 5-fluorouracil (FU), potentiating the activity of FU but reversing that of ethidium bromide in yeast and GPK. Also, the activity of the mitochondrial inhibitor oligomycin was reversed by the presence of gossypol in yeast cells but not tested in GPK. The uptake and retention of the mitochondria-specific dye rhodamine 123 were much depressed by gossypol in GPK. Gossypol showed little or no inhibitory effects in yeast or GPK in the presence of ethanol (0.2-0.5%). The drug was not mutagenic with respect to the yeast mitochondrial system. It was tentatively suggested that mitochondrial perturbation could explain the antifertility effect of gossypol if it is assumed that mitochondria have a special role to play in spermatogenesis and sperm motility, making these tissues more sensitive to mitochondrial inhibitors than somatic cells.