Structure-activity relationships in the myotoxicity of ring-methylated p-phenylenediamines in rats and correlation with autoxidation rates in vitro.

A number of N-methylated p-phenylenediamines are known to cause necrosis of skeletal and cardiac muscle in rats. The severity of the muscle damage induced by these compounds in vivo was found to be directly proportional to their autoxidation rates in vitro, suggesting that reactive species formed during oxidation may be involved in the initiation of this toxic effect. In the present study, the in vitro oxidation rates and in vivo toxicities of a number of ring-methylated p-phenylenediamines have been evaluated. 2,3,5,6-Tetramethyl p-phenylenediamine readily autoxidized at neutral pH. Hydrogen peroxide was formed in this reaction, while oxidation in the presence of glutathione or reduced pyridine nucleotides led to the production of both hydrogen peroxide and superoxide radical. Less highly methylated derivatives oxidized more slowly, with rates decreasing in the order 2,3,5,6-tetramethyl greater than 2,5-dimethyl greater than 2,6-dimethyl greater than 2-methyl. All these compounds were myotoxic in rats, with damage being largely confined to skeletal muscle. Toxicity was again proportional to oxidation rate. Myotoxicity appears to be a general property of certain substituted p-phenylenediamines and the structure-activity relationships identified may permit an estimate to be made of the potential toxicity of other compounds of this type.