Mitochondrial oxidation of p-phenylenediamine derivatives in vitro: Structure-activity relationships and correlation with myotoxic activity in vivo

A number of p-phenylenediamine derivatives are known to cause necrosis of skeletal and/or cardiac muscle when administered to experimental animals. Compounds of this type are oxidized to semiquinonedi-imines or quinonedi-imines by mitochondria in vitro, establishing alternative pathways for electron transport in the respiratory chain with concomitant decreases in respiratory control and ADP:O ratios. Muscle mitochondria were found to be particularly effective in promoting p-phenylenediamine oxidation in vitro and the magnitude of the mitochondrial effects of the various compounds tested correlated well with their ability to cause muscle necrosis in vivo. It is suggested that mitochondrial oxidation may be involved in the initiation of the myotoxic effects of these compounds and account for their target-site specificity.