Effects of long-term phenytoin treatment on brain weight and zinc and copper metabolism in rats.

The effects of phenytoin (PHT) treatment on brain weights and the zinc (Zn) and copper (Cu) concentrations in liver, kidney, and five parts of the brain have been studied in rats. After 32 wk of treatment (daily doses 72-88 mg/kg body weight), significantly reduced brain weights were found in rats sacrificed during treatment, but not in those sacrificed after 14 d of abstinence. The weight reduction mainly seemed to affect cortex, but cerebellum was also influenced. The PHT treatment during 18 wk did not significantly reduce the brain weights. At the end of treatment, significantly increased serum Cu concentrations were found, as well as decreased Zn levels in the liver and low Cu levels in the kidney. No large alterations were found in the trace element concentrations of different brain regions. The PHT treatment for 32 wk induced physical dependence, recorded as convulsions. It is suggested that PHT through a chelate binding with Zn and Cu interferes with the metabolism of the trace elements and the drug may cause a Zn deficiency. The observed decrease of the brain weights may have some parallel to the mental side effects of the drug observed during chronic epilepsy therapy.