title: Use of a systems model of drug-induced liver injury (DILIsym(®)) to elucidate the mechanistic differences between acetaminophen and its less-toxic isomer, AMAP, in mice.
abstract: Acetaminophen (APAP) has been used as a probe drug to investigate drug-induced liver injury (DILI). In mice, 3'-hydroxyacetanilide (AMAP), a less-toxic isomer of APAP, has also been studied as a negative control. Various mechanisms for the divergence in toxicological response between the two isomers have been proposed. This work utilized a mechanistic, mathematical model of DILI to test the plausibility of four mechanistic hypotheses. Simulation results were compared to an array of measured endpoints in mice treated with APAP or AMAP. The four hypotheses included: (1) quantitative differences in drug metabolism profiles as a result of different affinities for the relevant enzymes; (2) differences in the amount of reactive metabolites produced due to cytochrome P450 (CYP450) inhibition by the AMAP reactive metabolites; (3) differences in the rate of conjugation between the reactive metabolites and proteins; (4) differences in the downstream effects or potencies of the reactive metabolites on vital components within hepatocytes. The simulations did not support hypotheses 3 or 4 as the most likely hypotheses underlying the difference in hepatoxic potential of APAP and AMAP. Rather, the simulations supported hypotheses 1 and 2 (less reactive metabolite produced per mole of AMAP relative to APAP). Within the simulations, the difference in reactive metabolite formation was equally likely to have occurred from differential affinities for the relevant drug metabolism enzymes or from direct CYP450 inhibition by the AMAP reactive metabolite. The demonstrated method of using simulation tools to probe the importance of possible contributors to toxicological observations is generally applicable across species.
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes, 6 Davis Drive, Research Triangle Park, NC 27709, United States. Electronic address: bhowell@thehamner.org.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Howell
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes, 6 Davis Drive, Research Triangle Park, NC 27709, United States.
authors.forename: Scott Q
authors.initials: SQ
authors.lastname: Siler
authors.affiliation: The Hamner-UNC Institute for Drug Safety Sciences, The Hamner Institutes, 6 Davis Drive, Research Triangle Park, NC 27709, United States.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000082:Acetaminophen / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000083:Acetanilides / Q000737:chemistry / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D016227:Benzoquinones / Q000378:metabolism / Q000633:toxicity; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism; D003198:Computer Simulation; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D007097:Imines / Q000378:metabolism / Q000633:toxicity; D007536:Isomerism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D049490:Systems Biology / Q000379:methods*
chemical_list: D000083:Acetanilides; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C026137:3-hydroxyacetanilide; D019392:Cytochrome P-450 CYP2E1; C028473:N-acetyl-4-benzoquinoneimine
keywords: AMAP; Acetaminophen; Drug induced liver injury (DILI); Hepatotoxicity; Mechanistic model; Mice; Paracetamol; Pharmacokinetic/pharmacodynamic (PKPD) model; Reactive metabolite; Simulation