Mechanistic biomarkers in acetaminophen-induced hepatotoxicity and acute liver failure: from preclinical models to patients.
BACKGROUND
Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models into humans.


METHODS
We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermediates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury.


CONCLUSIONS
Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets.
University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics , 3901 Rainbow Blvd, MS 1018, Kansas City, KS 66160 , USA +1 913 588 7969 ; +1 913 588 7501 ; hjaeschke@kumc.edu.
Mitchell R
MR
McGill
Hartmut
H
Jaeschke
D000082:Acetaminophen / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000209:etiology* / Q000503:physiopathology; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D062787:Drug Overdose; D006801:Humans; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology
D015415:Biomarkers; D000082:Acetaminophen
acetaminophen; apoptosis; biomarkers; hepatotoxicity; inflammation; mechanisms; mitochondria; necrosis