Acetaminophen Induced Toxicity

Introduction

Acetaminophen (APAP) is an active ingredient in many over the counter painkillers, such as Tylenol and Oxycodone. APAP misuse is responsible for approximately 50% of acute liver failure cases in the United States (). Treatments for Acetaminophen Induced Liver Injury (AILI) are limited and ineffective if not caught early enough. Considering this and the widespread use of other prescription opioids, it is imperative that the mechanism of acetaminophen induced hepatotoxicity be revisited.

Two Electron Oxidation of APAP

The current accepted mechanism by which AILI presents itself is through a two electron oxidation as illustrated to the left. Under normal condtions, APAP is mostly converted to nontoxic metabollites via sulfation or glucuronidation while a small percentage is oxidized by cytochromes P-450 to the highly reactive metabollite, N-acetyl-p-benzoquinone imine (NAPQI) (). NAPQI is then detoxified through conjugation with glutathione (). During overdose, glucuronides and sulfates are saturated, leading to more NAPQI production, which results in hepatocellular supplies of glutathione becoming depleted as demand for the resource is higher than its regeneration (). The purported two electron oxidation product, NAPQI is then suggested to react with with cellular membranes, thus wreaking havoc and large scale hepatocyte damage and death ().

However, a single electron oxidation characterized by radical polymerization of APAP is more likely.

References

Potter, David W., Dwight W. Miller, and Jack A. Hinson. Identification of Acetaminophen Polymerization Products Catalyzed by Horseradish Peroxidase. Journal of Biological Chemistry, 260,22 (1985). 12174-2180. Print