METABOLISM AND DISPOSITION OF ACETAMINOPHEN: RECENT ADVANCES IN RELATION TO HEPATOTOXICITY AND DIAGNOSIS
By Mitchell R. McGill, H. Jaeschke. Pharmaceutical Research, 2013
634 citations recorded by the source corpus.
Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than 40 years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered.
Subfields: Oncology, Pharmacology
View Paper: https://www.semanticscholar.org/paper/72f4b0e1d06fe6252bcd5465e51bcd153096ad07
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Citations in the corpus
- Extending the Limits of Quantitative Proteome Profiling with Data-Independent Acquisition and Application to Acetaminophen-Treated Three-Dimensional Liver Microtissues (2015, background): “Additionally, glutathione S-transferases were induced, which are responsible of APAP-conjugation to glutathione (39).”
- Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update (2016, background): “synthesis and activity of CYP 2E1 and decreasing GSH stores and synthesis, thus enhancing liver necrosis and worsening prognosis.(5,8,21) Chronic alcoholism and APAP overdose may”