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.

Highlights

  • Acetaminophen (APAP) is a widely used analgesic and antipyretic drug

  • Survival test showed that only 20% (2/10) of adult males and 10% (1/10) of adult females were dead until 72 h after APAP (Fig. 1G,H)

  • Immature mice are more susceptible than adult mice to APAP-induced hepatocyte death

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Summary

Introduction

Acetaminophen (APAP) is a widely used analgesic and antipyretic drug. it is safe at therapeutic doses, APAP overdose induces acute liver injury[1,2,3]. Several studies demonstrate that hepatic receptor interacting protein (RIP)[1] and RIP3 activation is involved in hepatocyte death during APAP-induced acute liver injury[15,16,17,18]. Whether there are differences of the susceptibility between young children and adults to APAP-induced acute liver injury remains to be determined. The aim of the present study was to analyze the difference of the susceptibility between weanling immature mice and adult mice to APAP-induced acute liver injury. Our results showed that immature mice were more susceptible than adult mice to APAP-induced acute liver injury. Hepatic drug metabolic enzymes in immature mice than adult mice might partially contribute to the difference of the susceptibility to APAP-induced acute liver injury

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