Metabolomic analysis of acetaminophen induced subclinical liver injury

Abstract

Introduction: This study examines the metabolomic profile in humans following acetaminophen (APAP) induced subclinical hepatoxicity in the presence and absence of propylene glycol (PG), a cytochrome P450 2E1 inhibitor.

Methods: Plasma samples were collected during a previously performed randomized, cross-over trial where 21 subjects received APAP, four grams daily for two weeks in one arm and APAP, four grams daily with 20 mL PG in a second arm. Plasma collected at baseline and at day nine of each arm(time of peak elevation of liver function tests) underwent metabolomic analysis.

Results: There were reduced phase two metabolites in subjects who displayed liver injury. There was also decreased sulfonation capacity in all subjects as well as in subjects displaying liver injury relative to subjects not displaying liver injury as evidenced by decreased sulfonation of hepatically derived steroids. There were decreased levels of acylcarnitines in subjects who displayed liver injury relative to subjects not displaying liver injury, indicating inhibition of mitochondrial fatty acid β-oxidation.

Conclusions: Daily APAP dosing led to saturation of metabolic pathways and inhibition of mitochondrial function in subjects displaying subclinical liver injury.

Keywords:

• Acetaminophen
• hepatotoxicity
• propylene glycol
• metabolomics

Acknowledgements

We would also like to thank the nursing staff at the Clinical Research Center at the Beth Israel Deaconess Medical Center.

Disclosure statement

The authors report no conflict of interest.

Additional information

Funding

This work was funded by a grant from the William F. Milton Fund and Eleanor and Miles Shore Grant at Harvard Medical School.