Post-Treatment Protection with Piperonyl Butoxide Against Acetaminophen Hepatotoxicity is Associated with Changes in Selective but Not Total Covalent Binding

Abstract

Acetaminophen (APAP) induced hepatic centrilobular necrosis has been associated with cytochrome P-450-mediated generation of an electrophilic, reactive metabolite which covalently binds to cellular macromolecules as glutathione becomes depleted (Jollow, et al., 1973; Mitchell, et al., 1973a; 1973b; Potter, et al., 1973; 1974). Covalent binding has been well-correlated with the incidence and severity of liver necrosis and prior cytochrome P450 inhibition blocks both covalent binding and the atotoxicity (Jollow, et al., 1973; Potter, et al., 1973, 1974; Mitchell, et al., 1973a). In addition, administration of the cytochrome P-450 inhibitor, piperonyl butoxide (Pip B), 2 hrs after APAP, the time of maximal covalent binding (Jollow,et al., 1973, Ginsberg and Cohen, 1985) reduced the severity of liver damage (Brady, et al., 1988). The present study demonstrates that Pip B’s post-treatment protection is associated with alterations in selective protein arylation by APAP without a change in total covalent binding.