Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation

Background: CYP2E1, 1A2, and 3A4 have all been implicated in the formation of N-acetyl-p-benzoquinone imine (NAPQI), the reactive intermediate of acet aminophen (INN, paracetamol), in studies in human liver microsomes and comp lementary deoxyribonucleic acid-expressed enzymes, However, recent pharmaco kinetic evidence in humans has shown that the involvement of CYP1A2 is negl igible in vivo. The purpose of this study was to evaluate the respective ro les of CYP2E1 and 3A4 in vivo. Methods: The involvement of CYP2E1 was assessed through pretreatment of adu lt human volunteers with disulfiram to inhibit the enzyme and the role of C YP3A4 through its induction in a second cohort of adults with rifampin (INN , rifampicin). Each of the respective studies was an open-label, balanced-r andomized crossover design, Blood samples were obtained serially for 12 hou rs and urine was collected for 24 hours after acetaminophen administration, Acetaminophen was assayed in plasma, and acetaminophen and metabolites wer e assayed in urine. Results: The recovery of the thiol metabolites formed by conjugation of NAP QI with glutathione was decreased by 69%, and the formation clearance of NA PQI was decreased by 74% (both P < .01) by pre treatment with disulfiram. R ifampin pretreatment had no effect on the formation of NAPQI or the recover y of thiol metabolites formed by conjugation of NAPQI with glutathione, Conclusions: CYP2E1 accounts for the formation of NAPQI in intact humans; t he contribution of other isozymes of cytochrome P450 appears to be negligib le, Under some conditions, disulfiram may be useful in diminishing the form ation off NAPQI after acetaminophen overdose.