Abstract
The plant substance, lapachol, which is a hydroxyquinone, an antitumor agent, and an uncoupling agent, mimics the behaviour of the classical uncoupling agent 2, 4-dinitrophenol in the following manner. Firstly, an ATP energized mitochondrial volume change is induced by the combination of lapachol with showdomycin (a nonmercurial thiol reagent which is an antibiotic and also an antitumor agent). Secondly, an appropriate concentration of lapachol is capable of inhibiting the ATP energized mitochondrial volume change induced by gramicidin in the presence of the permeant ions potassium and L-malate. The further addition of showdomycin reinstates an effect of gramicidin. Thus lapachol exposes a strategically located mitochondrial thiol group which occupies a pivotal position between a cycle which meshes with the respiratory chain and a cycle which meshes with ATP. This role for lapachol is in agreement with our previous hypothesis that the cycle meshing with the respiratory chain involves quinones, hydroxyquinones and hydroquinones and that lapachol acting as a foreign hydroxyquinone interferes with this cycle and exposes the mitochondrial thiol group normally meshing with the cycle. The hydroxyquinone lawsone also mimics 2, 4-dinitrophenol. Lawsone is decidedly less effective than lapachol. Lawsone unlike lapachol does not possess an isopentenyl side chain. A simple test has been devised for selecting combinations of antitumor agents which act against a single intracellular target, such as mitochondria.
