Toxicodynamic aspects and new tools for assessing acetaminophen toxicity: a review

Acetaminophen (Tylenol®) or APAP is a widely used non-steroidal anti-inflammatory drug responsible for many cases of intoxication, suicide, and liver toxicity. Due to its toxicity mechanisms are not yet fully elucidated and this literature review aims to objectively bring some of the most recent and relevant scientific discoveries that can help in the understanding of the subject. After being ingested, paracetamol is absorbed and begins to be digested in the stomach, then being metabolized by the liver through phase I and phase II (glucuronyltransferases and sulfotransferases). When present in excess in the body, APAP forms an active metabolite known as N-acetyl-para-benzoquinone-imine (NAPQI). This metabolite is a reactive species capable of binding to living cells and proteins causing damages, which are largely responsible for injuries, especially in the liver. As a conclusion of this study, it can be inferred that the lesions caused by acetaminophen, in addition to protein adducts, also extend to mitochondria and proteins. New markers, in addition to enzymes already known from the CYP families, also include proteins and cytokines, in addition to molecular methods, messenger RNA and micro RNA have been used to study hepatotoxicity by APAP. This makes it easier to deeply understand the mechanisms of toxicity induced by acetaminophen and then to advance in studies with new therapies.

A Basis for the Decision to Rule in or out Acetaminophen Toxicity: Assessment of the Serum Level Within 4 Hours Post Overdose

Background: Acetaminophen is a popular antipyretic and analgesic medication worldwide; however, its therapeutic window is narrow, which may lead to overdose or toxicity. This study was conducted to assess the correlation between the serum acetaminophen levels before and 4 hours after the acute toxicity with this drug. The objective of this study was to test the validity of the serum level to arrive at a clinical decision on the toxicity with acetaminophen. Methods: This cross-sectional study was performed on patients hospitalized and treated with a diagnosis of acute acetaminophen overdose during one year (Sept. 2018 to Sept. 2019) at the Toxicology Department of Imam Reza Hospital, Mashhad, Iran. Patients were analyzed for demographics, time of ingestion, their first and second serum acetaminophen concentrations. Results: A total of 204 patients (106 male & 98 female) were included in this study. The average dose of acetaminophen ingestion by these patients was 14.5±3.50 g and all patients were treated successfully with N-Acetyl-Cysteine (NAC). The variables of age (P=0.293), serum acetaminophen levels at 1-2 h (P=0.679), and at 2-3 h (P=0.126) did not have significant relationships with the serum acetaminophen level on the fourth hour. However, the serum acetaminophen levels tested between 3-4 h and acetaminophen intoxication dosage had significant relationships with the acetaminophen level on the fourth hour. Conclusion: In patients with acute acetaminophen toxicity, the data on the serum levels obtained before a 4-hour timepoint from the ingestion were not useful to decide on the need for the rescue treatment with N-acetyl-cysteine.

The Protective Potential of Metformin against Liver Acetaminophen Toxicity

The inadequacy to replace acetaminophen (APAP) with a more effective analgesic continues its use in therapeutic interventions, upholding the risk of hepatotoxicity. Depletion of glutathione reserves by a metabolic intermediate of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), is the major reason. The current study presents the combinatorial effect of metformin, a biguanide, in ameliorating the APAP toxicity. HepG2 cells were used for in vitro studies and MTT and LDH leakage assays were used for viability assessment. 10 ?M of metformin improved the cell viability and membrane integrity of cells treated with a high antioxidant enzymes and reduced glutathione were significantly increased in cells co-administrated with metformin and acetaminophen