Phenytoin liver glutathione depletion. A possible mechanism of liver injury

Phenytoin produces significant liver glutathione depletion in vivo in mice. Pretreatment with inducers and inhibitors of drug metabolism show enhancement of phenytoin-induced glutathione depletion following phenobarbital and 3-methylcholanthrene pretreatment, inhibition of glutathione depletion following piperonyl butoxide, cobaltous chloride and alpha-naphthylisothiocyanate pretreatment (all drug metabolism inhibitors), and prevention of glutathione depletion following butylated hydroxytoluene pretreatment (both inducers of epoxide hydrolase). These data suggest that phenytoin-induced liver glutathione depletion may occur via a reactive metabolite and that this reactive metabolite possibly may be an epoxide.