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Abstract
BackgroundAcetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. APAP-CYS concentrations have been described in the setting of acute overdose, and a concentration >1.1 nmol/ml has been suggested as a marker of hepatic injury from acetaminophen overdose in patients with an ALT >1000 IU/L. However, the concentrations of APAP-CYS during therapeutic dosing, in cases of acetaminophen toxicity from repeated dosing and in cases of hepatic injury from non-acetaminophen hepatotoxins have not been well characterized. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose.MethodsSamples were collected during three clinical trials in which subjects received 4 g/day of acetaminophen and during an observational study of acetaminophen overdose patients. Trial 1 consisted of non-drinkers who received APAP for 10 days, Trial 2 consisted of moderate drinkers dosed for 10 days and Trial 3 included subjects who chronically abuse alcohol dosed for 5 days. Patients in the observational study were categorized by type of acetaminophen exposure (single or repeated). Serum APAP-CYS was measured using high pressure liquid chromatography with electrochemical detection.ResultsTrial 1 included 144 samples from 24 subjects; Trial 2 included 182 samples from 91 subjects and Trial 3 included 200 samples from 40 subjects. In addition, we collected samples from 19 subjects with acute acetaminophen ingestion, 7 subjects with repeated acetaminophen exposure and 4 subjects who ingested another hepatotoxin. The mean (SD) peak APAP-CYS concentrations for the Trials were: Trial 1- 0.4 (0.20) nmol/ml, Trial 2- 0.1 (0.09) nmol/ml and Trial 3- 0.3 (0.12) nmol/ml. APAP-CYS concentrations varied substantially among the patients with acetaminophen toxicity (0.10 to 27.3 nmol/ml). No subject had detectable APAP-CYS following exposure to a non-acetaminophen hepatotoxin.ConclusionsLower concentrations of APAP-CYS are detectable after exposure to therapeutic doses of acetaminophen and higher concentrations are detected after acute acetaminophen overdose and in patients with acetaminophen toxicity following repeated exposure.
Highlights
Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure
The metabolism of acetaminophen by CYP2E1 forms N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite that binds to cysteine residues in cellular proteins and forms acetaminophen protein adducts, referred to acetaminophen-cysteine (APAP-CYS) [1]
This product is detectable in serum for several days following acute overdose, and it has been proposed that detection of APAP-CYS is diagnostic of acetaminophen toxicity [4]
Summary
Acetaminophen-cysteine adducts (APAP-CYS) are a specific biomarker of acetaminophen exposure. The objective of this study is to describe APAP-CYS concentrations in these clinical settings as well as to further characterize the concentrations observed following acetaminophen overdose. Previous experimental work has shown that APAPCYS is formed within hepatocytes and released into the circulation following cell necrosis in the setting of acute acetaminophen toxicity [2,3]. This product is detectable in serum for several days following acute overdose, and it has been proposed that detection of APAP-CYS is diagnostic of acetaminophen toxicity [4]. The majority of the studies measuring APAP-CYS have included patients with known or suspected acute overdose of acetaminophen [4-7]
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