Mitochondrial alterations in the brain of the rat caused by chlorphentermine.

The effects of chlorphentermine on the bioenergetics and activity of monoamine oxidase in mitochondria from the brain of the rat were examined. Oxidation rates of glutamate and succinate were investigated in the presence of chlorphentermine (0.1-5.0 mM). In small concentrations (0.1-1.0 mM), chlorphentermine decreased the respiratory control ratio and the adenosine diphosphate oxygen (ADP/O) ratio, and stimulated state four respiration. State three respiration and the uncoupled state were also decreased, but to a lesser degree. In the presence of larger concentrations of chlorphentermine (1.0-5.0 mM), the respiration in states four, three, and in the uncoupled state, as well as the respiratory control ratio and ADP/O ratio, were decreased significantly. These data indicate that chlorphentermine functions as an uncoupler of oxidative phosphorylation. Oxidation of norepinephrine, serotonin, octopamine, tyramine and dopamine by monoamine oxidase (MAO), an enzyme marker of the outer mitochondrial membrane, was inhibited in the presence of 0.01 to 0.1 mM of chlorphentermine. Oxidation of tryptamine and benzylamine was unaffected. A kinetic study of the oxidation of serotonin in the absence and presence of chlorphentermine (0.025-0.1 mM) indicated that both the Vmax and Km were affected. This drug is an inhibitor of monoamine oxidase of mitochondria of the brain with mixed type inhibition. These combined data show that chlorphentermine affects biochemical processes in both inner and outer mitochondrial membranes.