The developing murine lung is susceptible to acetaminophen toxicity

Am J Physiol Lung Cell Mol Physiol. 2021 May 1;320(5):L969-L978. doi: 10.1152/ajplung.00072.2021. Epub 2021 Mar 24.


Acetaminophen (n-acetyl-p-aminophenol, APAP) use in the neonatal intensive care unit is rapidly increasing. Although APAP-related hepatotoxicity is rarely reported in the neonatal literature, other end-organ toxicity can occur with toxic exposures. APAP-induced lung injury has been reported with toxic exposures in adults, but whether this occurs in the developing lung is unknown. Therefore, we tested whether toxic APAP exposures would injure the developing lung. Neonatal C57BL/6 mice (PN7, early alveolar stage of lung development) were exposed to a dose of APAP known to cause hepatotoxicity in adult mice (280 mg/kg, IP). This exposure induced significant lung injury in the absence of identifiable hepatic toxicity. This injury was associated with increased pulmonary expression of Cyp2e1, the xenobiotic enzyme responsible for the toxic conversion of APAP. Exposure was associated with increased pulmonary expression of antioxidant response genes and decreased pulmonary glutathione peroxidase activity level. Furthermore, we observed an increase in pulmonary expression of proinflammatory cytokines and chemokines. Lastly, we were able to demonstrate that this toxic APAP exposure was associated with a shift in pulmonary metabolism away from glycolysis with increased oxidative phosphorylation, a finding consistent with increased mitochondrial workload, potentially leading to mitochondrial toxicity. This previously unrecognized injury and metabolic implications highlight the need to look beyond the liver and evaluate both the acute and long-term pulmonary implications of APAP exposure in the perinatal period.

Keywords: CYP2E1; acetaminophen; liver injury; lung injury; neonate; paracetamol.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetaminophen / adverse effects*
  • Acetaminophen / pharmacology
  • Animals
  • Cytochrome P-450 CYP2E1 / biosynthesis
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glycolysis / drug effects
  • Lung / growth & development*
  • Lung Injury / chemically induced
  • Lung Injury / metabolism*
  • Lung Injury / pathology
  • Male
  • Mice
  • Oxidative Phosphorylation / drug effects


  • Acetaminophen
  • Cytochrome P-450 CYP2E1
  • cytochrome P-450 2E1, mouse