Effect of Acetaminophen Against the Background of Alimentary Protein Deficiency on the Features of Sulfur-Containing Amino Acids Metabolism in Rats
Нalyna Kopylchuk* and Ivanna Nykolaichuk
Yuriy Fedkovych Chernivtsi National University, Educational and Scientific Institute of Biology, Chemistry and Bioresourses, Lesya Ukrainka, Ukraine
*Corresponding Author: Нalyna Kopylchuk, Yuriy Fedkovych Chernivtsi National University, Educational and Scientific Institute of Biology, Chemistry and Bioresourses, Lesya Ukrainka, Ukraine.
December 29, 2021; Published: January 24, 2022
In recent years, there has been extensive evidence of the involvement of disorders in the metabolism of sulfur-containing amino acids - methionine, cysteine and homocysteine - in the development of several diseases. These amino acids share common degradation pathways, and their intermediates play a role in regulating the activity of homocysteine remethylation and enzymes transsulfuration.
In this study, we aimed to evaluate the effect of acetaminophen on the background of dietary protein deficiency on the metabolism of sulfur-containing amino acids in rats: distribution of sulfur-containing amino acids - homocysteine, cysteine and methionine − in blood serum and hepatocytes, activity of key enzymes of the transsulfuration pathway of homocysteine metabolism - сystathionine beta-synthase, сystathionine gamma-lyase.
During the experiment, the experimental animals consumed a semi-synthetic diet AIN-93 in accordance with the recommendations of the American Institute of Nutrition. In order to model the alimentary protein deprivation rats received a low-protein diet daily for 28 days, which contained 1/3 of the generally accepted daily requirement of protein. After four weeks of keeping animals on an experimental diet, acute toxic damage with acetaminophen was modelled. The toxin was administered at 1250 mg/kg of animal weight as a suspension in a 2% solution of starch gel once a day for 2 days.
Our results indicate that the conditions of alimentary protein deprivation and acetaminophen toxic injury in hepatocytes and blood serum of animals disrupts the distribution of sulfur-containing amino acids (decrease in methionine, increase in cysteine concentration) with the development of hyperhomocysteinemia: in the absence of dietary protein - a mild form, with the introduction of toxic doses of acetaminophen - moderate.
The results confirm the causal relationship between the functioning of the transsulfuration pathway of homocysteine (decreased cystathionine β-synthase activity with simultaneous activation of cystathionine γ-lyase in animal hepatocytes) and the maximum increase in the level of this amino acid in blood serum under conditions of acetaminophen-toxic injury.
Elevated blood homocysteine levels can therefore be considered as a prognostic marker of functional abnormalities in the liver transsulfuration pathway and can be used in the diagnosis of hepatic pathologies.
Keywords: Amino Acids; Sulfur; Methionine; Cysteine; Homocysteine; Metabolism; Transsulfuration; Сystathionine Beta-Synthase; Сystathionine Gamma-Lyase; Acetaminophen; Alimentary Protein Deficiency; Liver; Rats
- Batool R., et al. “Protein-energy malnutrition: a risk factor for various ailments”. Critical Reviews in Food Science and Nutrition55 (2015): 242-553.
- Kitada M., et al. “The impact of dietary protein intake on longevity and metabolic health”. EBioMedicine 43 (2019): 632-640.
- Kopylchuk HP., et al. “Indexes of citrulline metabolism in rat liver under the toxic injury against the background of alimentary protein deficiency”. Ukrainian Biochemical Journal 92 (2020): 113-119.
- Morris CR., et al. “Acquired Amino Acid Deficiencies: A Focus on Arginine and Glutamine”. Nutrition in Clinical Practice 32 (2017): 30-47.
- Chiew AL., et al. “Interventions for paracetamol (acetaminophen) overdose”. Cochrane Database of Systematic Reviews (2018): CD003328.
- Aminoshariae A and Khan A. “Acetaminophen: old drug, new issues”. Journal of Endodontics 41 (2015): 588-593.
- Normandin PA., et al. “Hidden Danger: Pediatric Acetaminophen Overdose Unintentional and Intentional Emergencies”. Journal of Emergency Nursing 46 (2020): 914-922.
- Wongm A and Graudins A. “Risk prediction of hepatotoxicity in paracetamol poisoning”. Clinical Toxicology (Philadelphia) 55 (2017): 879-892.
- Ramachandran A and Jaeschke H. “Acetaminophen Hepatotoxicity”. Seminars in Liver Disease 39 (2019): 221-234.
- Popiolek I., et al. “Risk Factors for Hepatotoxicity Due to Paracetamol Overdose in Adults”. Medicina (Kaunas) 57 (2021): 752.
- Shader RI. “Acetaminophen (Paracetamol), COVID-19, and Misleading Conclusions: A Commentary”. Journal of Clinical Psychopharmacology 41 (2021): 98-99.
- Sestili P and Fimognari C. “Paracetamol-Induced Glutathione Consumption: Is There a Link with Severe COVID-19 Illness?” Frontiers in Pharmacology 11 (2020): 579944.
- Tan SHS., et al. “Medications in COVID-19 patients: summarizing the current literature from an orthopaedic perspective”. International Orthopaedics 44 (2020): 1599-1603.
- Zhou Z., et al. “Orostachys japonicus ameliorates acetaminophen-induced acute liver injury in mice”. Journal of Ethnopharmacology 265 (2021): 113392.
- Torres S., et al. “Endoplasmic Reticulum Stress-Induced Upregulation of STARD1 Promotes Acetaminophen-Induced Acute Liver Failure”. Gastroenterology 157 (2019): 552-568.
- McGill MR and Hinson JA. “The development and hepatotoxicity of acetaminophen: reviewing over a century of progress”. Drug Metabolism Reviews 52 (2020): 472-500.
- Guengerich FP. “Cytochrome P450 2E1 and its roles in disease”. Chemico-Biological Interactions 322 (2020): 109056.
- Djuric DM. “Editorial: Sulfur-Containing Amino Acids in Cardiovascular and Neural Physiology, Pathophysiology and Pharmacology: An Overview and Update”. Current Medicinal Chemistry 25 (2018): 322-323.
- Blachier F., et al. “Sulfur-Containing Amino Acids and Lipid Metabolism”. Journal of Nutrition 150 (2020): 2524-2531.
- Karmin O and Siow YL. “Metabolic Imbalance of Homocysteine and Hydrogen Sulfide in Kidney Disease”. Current Medicinal Chemistry 25 (2018): 367-377.
- Portillo F., et al. “Protein-protein interactions involving enzymes of the mammalian methionine and homocysteine metabolism”. Biochimie 173 (2020): 33-47.
- Škovierová H., et al. “The Molecular and Cellular Effect of Homocysteine Metabolism Imbalance on Human Health”. International Journal of Molecular Sciences 17 (2016): 1733.
- Qureshi SS., et al. “A novel approach in the management of hyperhomocysteinemia”. Medical Hypotheses 129 (2019): 109245.
- Kim J., et al. “Causes of hyperhomocysteinemia and its pathological significance”. Archives of Pharmacal Research 41 (2018): 372-383.
- Kopylchuk НР., et al. “The features of metabolic transformations of homocysteine and cysteine in rats’ hepatocytes under the nutritional imbalance. Scientific Herald of Chernivtsi University”. Biology (Biological Systems) 12 (2020): 141-149.
- Saande CJ., et al. “Dietary Egg Protein Prevents Hyperhomocysteinemia via Upregulation of Hepatic Betaine-Homocysteine S-Methyltransferase Activity in Folate-Restricted Rats”. Journal of Nutrition 149 (2019): 1369-1376.
- Pajares MA and Pérez-Sala D. “Mammalian Sulfur Amino Acid Metabolism: A Nexus Between Redox Regulation, Nutrition, Epigenetics, and Detoxification”. Antioxidant and Redox Signal 29 (2018): 408-452.
- Townsend DM., et al. “The importance of glutathione in human disease”. Biomedicine and Pharmacotherapy 57 (2003): 145-155.
- Jakubowski H. “Quality control in tRNA charging-editing of homocysteine”. Acta Biochimica Polonica 58 (2011): 149-163.
- Hayes D., et al. “Transport of L-[14C] cystine and L-[14C] cysteine by subtypes of high affinity glutamate transporters over-expressed in HEK cells”. Neurochemistry International 46 (2005): 585-594.
- Randeva HS. “Hormonal Regulation of Homocysteine”. Metabolic Syndrome and Related Disorders 1 (2003): 121-128.
- Adinolfi LE., et al. “Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients”. Hepatology 41 (2005): 995-1003.
- Bublil EM and Majtan T. “Classical homocystinuria: From cystathionine beta-synthase deficiency to novel enzyme therapies”. Biochimie 173 (2020): 48-56.
- Chen H., et al. PLoS One 8 (2013): e76900.
- Wang M., et al. “The effect of certain conditions in the regulation of cystathionine γ-lyase by exogenous hydrogen sulfide in mammalian cells”. Biochemical Genetics 51 (2013): 503-513.
- Carsten AW. “Hydrogen sulfide a new gaseous signal molecule and blood pressure regulator”. Journal of Nephrology 22 (2009): 173-175.
- Reeves PG., et al. “AIN-93 purified diets for laboratory rodents: final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet”. Journal of Nutrition11 (1993): 1939-1951.
- Kravchenko L., et al. “A simple non-enzymatic method for the isolation of high yields of functional rat hepatocytes”. Cell Biology International 26 (2002): 1003-1006.
- Zaichko N., et al. “Influence of acute methionine hyperhomocysteinemia on hydrogen sulfide formation in organs of rats and its correction by the complex of vitamins B6, B9, B12. Eksperymentalna ta klinichna fiziolohiia i biokhimiia 4 (2009): 29-35.
- Murphy ME and Kehrer JP. “Oxidation State of Tissue Thiol Groups and Content of Protein Carbonyl Groups in Chickens with Inherited Muscular Dystrophy”. Biochemical Journal 260 (1998): 359-364.