Research Progress on N-Acetyl-4-Aminophenol and Its Toxic Effects
Keywords:
N-Acetyl-4-Aminophenol, Physical and Chemical Properties, Toxic Effects
Abstract
N-Acetyl-4-aminophenol (NA4AP) is one of the analgesic and antipyretic drugs found in a large number of over-the-counter medications and is widely used worldwide because of its analgesic and antipyretic effects and because of its rapid and prolonged duration of action. Due to the large amount of use of NA4AP, it has already polluted the environment, such as groundwater, soil, surface water, etc., and it is difficult to be degraded in the natural environment, so the potential threat of NA4AP to human health has aroused people's concern. This paper reviews NA4AP and its physicochemical properties; development process; absorption, metabolism, excretion; toxic effects, etc., to provide a scientific basis for the use and control of NA4AP in China and many countries in the world.
References
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[3] Yang, Q., He, W. H., Xie, L., et al. (2024). Oral administration of astilbin mitigates acetaminophen-induced acute liver injury in mice by modulating the gut microbiota. Acta Pharmacologica Sinica, 46(2), 416–429. https://doi.org/10.1038/s41401-024-01383-9
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[5] Sun, J., Luo, Q., Wang, D., et al. (2015). Occurrences of pharmaceuticals in drinking water sources of major river watersheds, China. Ecotoxicology and Environmental Safety, 117, 132–140. https://doi.org/10.1016/j.ecoenv.2015.03.032
[6] Letsinger, S., Kay, P., Rodríguez-Mozaz, S., et al. (2019). Spatial and temporal occurrence of pharmaceuticals in UK estuaries. Science of the Total Environment, 678, 74–84. https://doi.org/10.1016/j.scitotenv.2019.04.182
[7] Ramírez-Morales, D., Masís-Mora, M., Montiel-Mora, J. R., et al. (2024). Pharmaceuticals, hazard and ecotoxicity in surface and wastewater in a tropical dairy production area in Latin America. Chemosphere, 346, 140443. https://doi.org/10.1016/j.chemosphere.2023.140443
[8] National Center for Biotechnology Information. (2023). PubChem Compound Summary for CID 1983, Acetaminophen. https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen
[9] Espinosa Bosch, M., Ruiz Sánchez, A. J., Sánchez Rojas, F., et al. (2006). Determination of paracetamol: Historical evolution. Journal of Pharmaceutical and Biomedical Analysis, 42(3), 291–321. https://doi.org/10.1016/j.jpba.2006.04.007
[10] Dierkes, G., Weiss, T., Modick, H., et al. (2014). N-Acetyl-4-aminophenol (paracetamol), N-acetyl-2-aminophenol and acetanilide in urine samples from the general population, individuals exposed to aniline and paracetamol users. International Journal of Hygiene and Environmental Health, 217(4–5), 592–599. https://doi.org/10.1016/j.ijheh.2013.11.005
[11] Okeke, P., & Ihejirika, C. D. A.-A. (2020). Concerns as more Nigerians use paracetamol to cook meat. Newsp Publ.
[12] Alemany, S., Avella-García, C., Liew, Z., et al. (2021). Prenatal and postnatal exposure to acetaminophen in relation to autism spectrum and attention-deficit and hyperactivity symptoms in childhood: Meta-analysis in six European population-based cohorts. European Journal of Epidemiology, 36(10), 993–1004. https://doi.org/10.1007/s10654-021-00754-4
[13] Ma, R., Wang, B., Yin, L., et al. (2017). Characterization of pharmaceutically active compounds in Beijing, China: Occurrence pattern, spatiotemporal distribution and its environmental implication. Journal of Hazardous Materials, 323, 147–155. https://doi.org/10.1016/j.jhazmat.2016.05.030
[14] Picó, Y., Campo, J., Alfarhan, A. H., et al. (2021). A reconnaissance study of pharmaceuticals, pesticides, perfluoroalkyl substances and organophosphorus flame retardants in the aquatic environment, wild plants and vegetables of two Saudi Arabia urban areas: Environmental and human health risk assessment. Science of the Total Environment, 776, 145843. https://doi.org/10.1016/j.scitotenv.2021.145843
[15] Iram, S., Nazar, Z., Sajid, M., et al. (2024). In-tube solid phase extraction with graphitic-based polyurethane sponge as a superhydrophobic sorbent and determination of drug residues in foodstuffs using high-performance liquid chromatography. Food Chemistry, 448, 139022. https://doi.org/10.1016/j.foodchem.2024.139022
[16] Vazquez-Roig, P., Andreu, V., Blasco, C., et al. (2012). Risk assessment on the presence of pharmaceuticals in sediments, soils and waters of the Pego-Oliva Marshlands (Valencia, eastern Spain). Science of the Total Environment, 440, 24–32. https://doi.org/10.1016/j.scitotenv.2012.08.036
[18] Xie, H., Hao, H., Xu, N., et al. (2019). Pharmaceuticals and personal care products in water, sediments, aquatic organisms, and fish feeds in the Pearl River Delta: Occurrence, distribution, potential sources, and health risk assessment. Science of the Total Environment, 659, 230–239. https://doi.org/10.1016/j.scitotenv.2018.12.222
[20] Adedipe, D. T., Chen, C., Lai, R. W. S., et al. (2024). Occurrence and potential risks of pharmaceutical contamination in global estuaries: A critical review and analysis. Environment International, 192, 109031. https://doi.org/10.1016/j.envint.2024.109031
[21] Prescott, L. F. (1980). Kinetics and metabolism of paracetamol and phenacetin. British Journal of Clinical Pharmacology, 10(Suppl 2), 291s–298s. https://doi.org/10.1111/j.1365-2125.1980.tb01812.x
[22] Li, X., Xu, L., Wan, Y., et al. (2022). Urinary paracetamol (4-acetaminophenol) and its isomer 2-acetaminophenol of Chinese pregnant women: Exposure characteristics and association with oxidative stress biomarkers. Science of the Total Environment, 852, 158375. https://doi.org/10.1016/j.scitotenv.2022.158375
[23] Henríquez-Hernández, L. A., Macías-Montes, A., Acosta-Dacal, A., et al. (2022). Human biomonitoring of persistent and non-persistent pollutants in a representative sample of the general population from Cape Verde: Results from the PERVEMAC-II study. Environmental Pollution, 306, 119331. https://doi.org/10.1016/j.envpol.2022.119331
[24] Tamaki, R., Noshiro, K., Furugen, A., et al. (2024). Breast milk concentrations of acetaminophen and diclofenac – unexpectedly high mammary transfer of the general-purpose drug acetaminophen. BMC Pregnancy and Childbirth, 24(1), 90. https://doi.org/10.1186/s12884-024-06287-4
[25] Ji, Y., Azuine, R. E., Zhang, Y., et al. (2020). Association of cord plasma biomarkers of in utero acetaminophen exposure with risk of attention-deficit/hyperactivity disorder and autism spectrum disorder in childhood. JAMA Psychiatry, 77(2), 180–189. https://doi.org/10.1001/jamapsychiatry.2019.3259
[26] Baker, B. H., Lugo-Candelas, C., Wu, H., et al. (2020). Association of prenatal acetaminophen exposure measured in meconium with risk of attention-deficit/hyperactivity disorder mediated by frontoparietal network brain connectivity. JAMA Pediatrics, 174(11), 1073–1081. https://doi.org/10.1001/jamapediatrics.2020.3080
[27] Bessems, J. G., & Vermeulen, N. P. (2001). Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Critical Reviews in Toxicology, 31(1), 55–138. https://doi.org/10.1080/20014091111677
[28] Ye, H., Nelson, L. J., Gómez Del Moral, M., et al. (2018). Dissecting the molecular pathophysiology of drug-induced liver injury. World Journal of Gastroenterology, 24(13), 1373–1385. https://doi.org/10.3748/wjg.v24.i13.1373
[29] Caparrotta, T. M., Antoine, D. J., & Dear, J. W. (2018). Are some people at increased risk of paracetamol-induced liver injury? A critical review of the literature. European Journal of Clinical Pharmacology, 74(2), 147–160. https://doi.org/10.1007/s00228-017-2356-6
[30] Cipolat, L., Loeb, O., Latarche, C., et al. (2017). [Acetaminophen: Knowledge, use and overdose risk in urban patients consulting their general practitioner. A prospective, descriptive and transversal study]. Therapie, 72(4), 453–463. https://doi.org/10.1016/j.therap.2016.12.012
[31] Blieden, M., Paramore, L. C., Shah, D., et al. (2014). A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Review of Clinical Pharmacology, 7(3), 341–348. https://doi.org/10.1586/17512433.2014.904744
[32] Walker, V., Mills, G. A., Anderson, M. E., et al. (2017). The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis. Xenobiotica, 47(2), 164–175. https://doi.org/10.3109/00498254.2016.1166533
[33] Johnson, B. P., Walisser, J. A., Liu, Y., et al. (2014). Hepatocyte circadian clock controls acetaminophen bioactivation through NADPH-cytochrome P450 oxidoreductase. Proceedings of the National Academy of Sciences of the United States of America, 111(52), 18757–18762. https://doi.org/10.1073/pnas.1421708111
[34] Bertolini, A., Ferrari, A., Ottani, A., et al. (2006). Paracetamol: New vistas of an old drug. CNS Drug Reviews, 12(3–4), 250–275. https://doi.org/10.1111/j.1527-3458.2006.00250.x
[35] Kon, K., Kim, J. S., Jaeschke, H., et al. (2004). Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology, 40(5), 1170–1179. https://doi.org/10.1002/hep.20437
[36] Lai, Y., & Zhong, X. B. (2024). Special section on mechanisms of drug metabolism in acetaminophen-induced hepatotoxicity-editorial. Drug Metabolism and Disposition, 52(8), 704–706. https://doi.org/10.1124/dmd.124.001848
[37] Yiang, G. T., Yu, Y. L., Lin, K. T., et al. (2015). Acetaminophen induces JNK/p38 signaling and activates the caspase-9-3-dependent cell death pathway in human mesenchymal stem cells. International Journal of Molecular Medicine, 36(2), 485–492. https://doi.org/10.3892/ijmm.2015.2254
[38] Ishitsuka, Y., Kondo, Y., & Kadowaki, D. (2020). Toxicological property of acetaminophen: The dark side of a safe antipyretic/analgesic drug. Biological and Pharmaceutical Bulletin, 43(2), 195–206. https://doi.org/10.1248/bpb.b19-00722
[39] Perneger, T. V., Whelton, P. K., & Klag, M. J. (1994). Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. New England Journal of Medicine, 331(25), 1675–1679. https://doi.org/10.1056/NEJM199412223312502
[40] Türk Özterlemez, N., Inan, N., Arslan, M., et al. (2024). Effects of repeated doses of paracetamol administration during pregnancy on lung, kidney, and liver tissues of pregnant rats. Agri, 36(3), 137–145. https://doi.org/10.14744/agri.2023.90688
[41] Alshahrani, S., Ashafaq, M., Hussain, S., et al. (2021). Renoprotective effects of cinnamon oil against APAP-Induced nephrotoxicity by ameliorating oxidative stress, apoptosis and inflammation in rats. Saudi Pharmaceutical Journal, 29(2), 194–200. https://doi.org/10.1016/j.jsps.2021.01.002
[42] Hart, S. G., Beierschmitt, W. P., Wyand, D. S., et al. (1994). Acetaminophen nephrotoxicity in CD-1 mice. I. Evidence of a role for in situ activation in selective covalent binding and toxicity. Toxicology and Applied Pharmacology, 126(2), 267–275. https://doi.org/10.1006/taap.1994.1116
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[44] Catumbela, C. S. G., & Morales, R. (2024). Elderly mice with history of acetaminophen intoxication display worsened cognitive impairment and persistent elevation of astrocyte and microglia burden. Scientific Reports, 14(1), 14205. https://doi.org/10.1038/s41598-024-65185-z
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