Acetaminophen

Acetaminophen (paracetamol) is a selective cyclooxygenase-2 (COX-2) inhibitor with an IC50 of 25.8 μM; is a widely used antipyretic and analgesic drug.

In Vitro:In vitro, acetaminophen elicites a 4.4-fold selectivity toward COX-2 inhibition (IC50 113.7 μM for COX-1; IC50 25.8 μM for COX-2). Following oral administration of the drug, maximal ex vivo inhibitions are 56% (COX-1) and 83% (COX-2). Acetaminophen plasma concentrations remaine above the in vitro IC50 for COX-2 for at least 5 h postadministration. Ex vivo IC50 values (COX-1: 105.2 μM; COX-2: 26.3 μM) of acetaminophen compared favorably with its in vitro IC50 values. In contrast to previous concepts, acetaminophen inhibited COX-2 by more than 80%, i.e., to a degree comparable to nonsteroidal antiinflammatory drugs (NSAIDs) and selective COX-2 inhibitors. However, a >95% COX-1 blockade relevant for suppression of platelet function is not achieved[1]. MTT assay shows that Acetaminophen (APAP) in a dose of 50 mM significantly (p<0.001) reduces cell viability to 61.5±6.65%. Interestingly, the significant (p<0.01) increase in cell viability to 79.7±2.47% is observed in the Acetaminophen/HV110 co-treated cells, compared to Acetaminophen treated cells[2].

In Vivo:Administering Acetaminophen (250 mg/kg, orally) to the mice causes significant (p<0.001) liver damage and necrosis of cells as evidenced by the elevated serum hepatic enzymes alanine aminotransferase (ALT), aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (γGT) compared with normal group. Conversely, effects of pretreatment with different doses of citral (125, 250, and 500 mg/kg) exhibited a significant (p<0.05) decrease in serum activities of ALT (91.79%, 93.07%, and 95.61%, resp.), AST (93.40%, 91.89%, and 96.52%, resp.), ALP (39.29%, 37.07%, and 59.80%, resp.), and γGT (92.83%, 91.59%, and 93.0%, resp.), when compared to the Acetaminophen group. Similar results were found in pretreatment with SLM on the activity of ALT (95.90%), AST (95.03%), ALP (70.52%), and γGT (92.69%)[3].

References:
[1]. Hinz, B, et al. Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man. FASEB J, 2008. 22(2): p. 383-90. [2]. Dini? M, et al. Lactobacillus fermentum Postbiotic-induced Autophagy as Potential Approach for Treatment ofAcetaminophen Hepatotoxicity. Front Microbiol. 2017 Apr 6;8:594. [3]. Uchida NS, et al. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice. Evid Based Complement Alternat Med. 2017;2017:1796209.

Multi-targeted protection of acetaminophen-induced hepatotoxicity in mice by tannic acid.[Pubmed:28376392]

Int Immunopharmacol. 2017 Jun;47:95-105.

Tannic acid (TA) is the polyphenol that has beneficial health effects against oxidative stress. However, the hepatoprotective effects of TA are still relatively unknown. In the present study, we evaluated the effects of TA on an Acetaminophen (APAP)-induced hepatotoxicity model, which was established by administration of 400mg/kg of APAP. The levels of alanine transferase (ALT), aspartate transferase (AST), dendothelin-1 (ET-1), nitric oxide (NO) and malondialdehyde (MDA) in the APAP-induced hepatotoxicity mice were significantly increased (up to ~200%), while their levels were reduced by pretreatment with TA (25 and 50mg/kg) (P<0.05). The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) in the APAP-induced hepatotoxicity mice were significantly reduced (lower to ~65%), while their activities were increased by pretreatment with TA (25 and 50mg/kg) (P<0.05). In addition, pretreatment with oral TA (25 and 50mg/kg) for 3days before the APAP administration dose-dependently ameliorated changes in hepatic histopathology, suppressed overexpression of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), c-fos, c-jun, NF-kappaB (p65) and caspase-3 (all P<0.05), downregulated bax and upregulated bcl-2, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) (all P<0.05) in the liver. These results indicate that TA exhibits significant hepatoprotective effects against APAP-induced hepatotoxicity and suggest that the hepatoprotective mechanisms of TA may be related to anti-oxidation, anti-inflammation and anti-apoptosis.

Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice.[Pubmed:28366990]

J Clin Biochem Nutr. 2017 Mar;60(2):115-120.

Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of Acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on Acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of Acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of gamma-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with Acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with Acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented Acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against Acetaminophen-induced hepatotoxicity in mice.

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.[Pubmed:12242329]

Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13926-31.

Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an approximately 5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as Acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

Effect of acetaminophen on atherosclerosis.[Pubmed:11724102]

Ann Pharmacother. 2001 Nov;35(11):1476-9.

OBJECTIVE: To evaluate the antioxidant effects of Acetaminophen in atherosclerosis. DATA SOURCES: Experimental literature and abstracts accessed through MEDLINE (1966-February 2001). DATA SYNTHESIS: Atherosclerosis is an inflammatory disorder associated with coronary events. The oxidative stress burden resulting from excess pro-oxidant free radical formation contributes to oxidative modification of low-density lipoprotein (lipid peroxidation) and is associated with atherosclerosis. Acetaminophen (phenol-like compound) may limit these key processes that are involved. The findings of earlier experimental laboratory tests and abstracts are evaluated. CONCLUSIONS: In vitro data suggest that Acetaminophen may reduce lipid peroxidation, whereas animal data showed decreased progression of atherosclerosis. Further animal model and human studies are required to confirm these earlier findings.

Comparison of the cyclooxygenase-1 inhibitory properties of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors, using sensitive microsomal and platelet assays.[Pubmed:9365818]

Can J Physiol Pharmacol. 1997 Sep;75(9):1088-95.

Two forms of cyclooxygenase (COX) activity are involved in the synthesis of prostaglandins, prostacyclins, and thromboxanes in mammalian cells. There is now convincing evidence, obtained with a number of structurally distinct inhibitors, that selective COX-2 inhibitors possess anti-inflammatory effects with an improved gastrointestinal tolerability compared with conventional nonsteroidal anti-inflammatory drugs (NSAIDs) affecting both COX-1 and COX-2. As more selective COX-2 inhibitors are being developed, assays with a high degree of sensitivity to inhibition are needed to compare the relative effects of compounds on COX-1 activity. In the present report, we describe a sensitive assay for the inhibition of human COX-1 based on the production of prostaglandin E2 by microsomes from U937 cells incubated with a subsaturating concentration of arachidonic acid. More than 45 NSAIDs and selective COX-2 inhibitors were tested in this assay. IC50 values ranged from 1 nM for flunixin and flurbiprofen to about 200-500 microM for salicylate and Acetaminophen. Potent and nonselective NSAIDs such as sulindac sulfide, diclofenac, and indomethacin showed IC50 values of < 20 nM. Among the compounds that have been reported to show selectivity for COX-2, the rank order of potency against COX-1 was DuP 697 > SC-58451 > celecoxib > nimesulide-meloxicam-piroxicam-NS-398-RS-57067 > SC-57666 > SC-58125 > flosulide > etodolac > L-745,337 > DFU-T-614, with IC50 values ranging from 7 nM to 17 microM. A good correlation was obtained between the IC50 values for the inhibition of microsomal COX-1 and both the inhibition of TXB2 production by Ca2+ ionophore challenged platelets and the inhibition of prostaglandin E2 production by CHO cells stably expressing human COX-1. However, the microsomal assay was more sensitive to inhibition than cell-based assays and allowed the detection of inhibitory effects on COX-1 for all NSAIDs and selective COX-2 inhibitors examined with discrimination of their potency under conditions of limited availability of arachidonic acid.

Acetaminophen (paracetamol) is a selective cyclooxygenase-2 (COX-2) inhibitor with an IC50 of 25.8 μM; is a widely used antipyretic and analgesic drug. Acetaminophen is a potent hepatic N-acetyltransferase 2 (NAT2) inhibitor.

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