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The paradoxical protective effect of malnutrition in acetaminophen-induced liver injury

Vinitha D'Souza1, Varsha Augustin1, Madhura R J1

  • 1Nitte Gulabi Shetty Institute of Pharmaceutical Sciences, Nitte University, Mangalore, India.

Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
|June 12, 2026
PubMed
Abstract

Insights

Protein malnutrition (PMN) surprisingly protected against acetaminophen (APAP)-induced liver injury (AILI) in mice. This suggests nutritional status significantly impacts drug toxicity, potentially explaining fewer overdose deaths in developing countries.

Area of Science:

  • Hepatology
  • Toxicology
  • Nutritional Science

Background:

  • Drug-induced liver injury (DILI) is often exacerbated by malnutrition.
  • The specific impact of protein malnutrition (PMN) on acetaminophen (APAP)-induced liver injury (AILI) is not well understood, especially in low and middle-income countries (LMICs).
  • PMN is prevalent in LMICs, necessitating research into its effects on AILI.

Purpose of the Study:

  • To investigate the influence of PMN on the severity of AILI in a murine model.
  • To elucidate the mechanisms underlying the interaction between nutritional status and APAP hepatotoxicity.

Main Methods:

  • Female BALB/c mice were fed either a low protein diet (LPD, 10% protein) or a normal diet (ND, 18% protein) to induce PMN or serve as controls.
  • Mice were challenged with varying doses of APAP to assess lethality and liver injury markers.
  • Evaluations included liver injury markers (ALT, AST, ALP), oxidative stress, inflammatory cytokines (TNF-α, IL-6), CYP2E1 activity, histopathology, PCNA expression, and pharmacokinetic (PK) analysis.

Main Results:

  • Mice on the LPD exhibited reduced lethality and liver injury (lower ALT, AST, ALP) compared to ND mice following APAP challenge.
  • ND mice showed increased oxidative stress, higher inflammatory cytokine levels, elevated PCNA expression, and more severe histological damage.
  • PK analysis revealed altered APAP metabolism in LPD mice, with greater CYP enzyme expression and activity observed in ND mice, indicating enhanced APAP bioactivation.

Conclusions:

  • Contrary to expectations, protein malnutrition conferred protection against APAP-induced liver injury and lethality in mice.
  • The findings suggest that PMN may contribute to fewer acetaminophen overdose-related deaths observed in developing countries.
  • Further research into the molecular mechanisms of nutritional influences on drug metabolism and liver injury is crucial.
Keywords:
AcetaminophenAnti-oxidant assayCYP enzymeLiver injuryNutritional statusPharmacokinetics

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