title: Immature mice are more susceptible than adult mice to acetaminophen-induced acute liver injury.
abstract: Acetaminophen (APAP) overdose induces acute liver injury. The aim of the present study was to analyze the difference of susceptibility between immature and adult mice to APAP-induced acute liver injury. Weanling immature and adult mice were injected with APAP (300 mg/kg). As expected, immature mice were more susceptible than adult mice to APAP-induced acute liver injury. APAP-evoked hepatic c-Jun N-terminal kinase phosphorylation was stronger in immature mice than in adult mice. Hepatic receptor-interacting protein (RIP)1 was obviously activated at APAP-exposed immature and adult mice. Interestingly, hepatic RIP3 activation was more obvious in APAP-treated immature mice than adult mice. Although there was no difference on hepatic GSH metabolic enzymes between immature and adult mice, immature mice were more susceptible than adult mice to APAP-induced hepatic GSH depletion. Of interest, immature mice expressed a much higher level of hepatic Cyp2e1 and Cyp3a11 mRNAs than adult mice. Correspondingly, immature mice expressed a higher level of hepatic CYP2E1, the key drug metabolic enzyme that metabolized APAP into the reactive metabolite NAPQI. These results suggest that a higher level of hepatic drug metabolic enzymes in immature mice than adult mice might contribute to the difference of susceptibility to APAP-induced acute liver injury.
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.|Anhui Provincial Key Laboratory of Population Health &Aristogenics, Anhui Medical University, Hefei, 230032, China.|Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.|Anhui Provincial Key Laboratory of Population Health &Aristogenics, Anhui Medical University, Hefei, 230032, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei, 230032, China.|Anhui Provincial Key Laboratory of Population Health &Aristogenics, Anhui Medical University, Hefei, 230032, China.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D020690:GTPase-Activating Proteins; D008565:Membrane Proteins; C490620:Ralbp1 protein, mouse; D000082:Acetaminophen; D019392:Cytochrome P-450 CYP2E1; C000617651:cytochrome P-450 2E1, mouse; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C485615:Ripk3 protein, mouse; D005978:Glutathione