Acetaminophen-d₃

Acetaminophen-d₃ is intended for use as an internal standard for the quantification of acetaminophen (Item No. 10024) by GC- or LC-MS. Acetaminophen is an analgesic and antipyretic compound.^1,2 Unlike many NSAIDs, which inhibit both COX-1 and COX-2, early studies suggested that acetaminophen is a poor inhibitor of both isoforms.^3,4 However, it does inhibit COX-2 by 83% and COX-1 by 56% in human blood ex vivo, albeit at a high 1,000 mg dose, with IC₅₀ values of 25.8 and 113.7 µM, respectively.⁵ Acetaminophen is enzymatically and non-enzymatically converted to several reactive metabolites that contribute to adverse or indirect effects, including liver injury.^6,7,8 At toxic doses, the acetaminophen metabolite N-acetyl-4-benzoquinone imine (NAPQI; Item No. 16115) depletes glutathione reserves in the liver, leading to an accumulation of NAPQI and subsequent hepatocyte necrosis.⁹ Acetaminophen decreases glutathione levels and reduces glutathione peroxidase activity in mice when administered at a dose of 250 mg/kg and induces ferroptotic cell death in primary mouse hepatocytes, an effect that can be blocked by the ferroptosis inhibitor ferrostatin-1 (Item No. 17729).^10,11 Acetaminophen has analgesic and antipyretic properties in animal models.^1,2

WARNING This product is not for human or veterinary use.

1. Vinegar, R., Truax, J.F., and Selph, J.L. Quantitative comparison of the analgesic and anti-inflammatory activities of aspirin, phenacetin and acetaminophen in rodents. Eur. J. Pharmacol. 37(1), 23-30 (1976).

2. Kobayashi, S., and Takagi, H. Fever responses to bacterial pyrogens in guinea pigs and application for screening of antipyretic agents. Jpn. J. Pharmacol. 18(1), 80-85 (1968).

3. Mitchell, J.A., Akarasereenont, P., Thiemermann, C., et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl. Acad. Sci. USA 90(24), 11693-11697 (1993).

4. Warner, T.D., Giuliano, F., Vojnovic, I., et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc. Natl. Acad. Sci. USA 96(13), 7563-7568 (1999).

5. Hinz, B., Cheremina, O., and Brune, K. Acetaminophen (paracetamol) is a selective cyclooxygenase-2- inhibitor in man. The FASEB Journal 22(2), 383-390 (2007).

6. Hinson, J.A. Reactive metabolites of phenacetin and acetaminophen: A review. Environ. Health Perspect. 49, 71-79 (1983).

7. Högestätt, E.D., Jönsson, B.A.G., Ermund, A., et al. Conversion of acetaminophen to the biactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system. The Journal of Biological Chemisty 280(36), 31405-31412 (2005).

8. Han, D., Dara, L., Win, S., et al. Regulation of drug-induced liver injury by signal transduction pathways: Critical role of mitochondria. Trends Pharmacol. Sci. 34(4), 243-253 (2013).

9. Qiu, Y., Benet, L.Z., and Burlingame, A.L. Identification of the hepatic protein targets of reactive metabolites of acetaminophen in vivo in mice using two-dimensional gel electrophoresis and mass spectrometry. The Journal of Biological Chemisty 273(28), 17940-17953 (1998).

10. Tirmenstein, M.A., and Nelson, S.D. Acetaminophen-induced oxidation of protein thiols. Contribution of impaired thiol-metabolizing enzymes and the breakdown of adenine nucleotides. The Journal of Biological Chemisty 265(6), 3059-3065 (1990).

11. Lőrincz, T., Jemnitz, K., Kardon, T., et al. Ferroptosis is involved in acetaminophen induced cell death. Pathol. Oncol. Res. 21(4), 1115-1121 (2015).