Effect of Dietary Protein Deficiency on the Activity of Cytochrome P450 Enzyme Systems in the Liver of Rats of Reproductive Age Under Acetaminophen-Induced Injury

Нalyna Kopylchuk*, Ivanna Nykolaichuk and Маriia Ursatyi

Yuriy Fedkovych Chernivtsi National University, Ukraine Educational and Scientific institute of Biology, Chemistry and Bioresources, Ukraine

*Corresponding Author: Нalyna Kopylchuk, Yuriy Fedkovych Chernivtsi National University, Ukraine; Educational and scientific institute of Biology, Chemistry and Bioresources, Ukraine.

Received: February 28, 2022; Published: March 15, 2022

Preface

In this study, we aimed to evaluate the effect of dietary protein deficiency on the activity of cytochrome P450 enzyme systems - p-hydroxylation, N-demethylation, N-oxidation in the liver of rats of reproductive age under acetaminophen-induced injury. Within this topic, we investigated the content of cytochrome P450 and the rate of its inactivation in the inactive form of P420, as well as the intensity of generation of superoxide anion radical under experimental conditions.

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 injury 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.

We found that acetaminophen toxic injury in the study group of rats leads to an increase in CYP450 and significant activation of microsomal monooxygenases in the liver with a simultaneous redistribution of hydroxylation and oxidation reactions in favor of oxidative N-dealkylation and N-oxidation, accompanied by excessive formation of NAPQI as opposed to non-toxic 3-OH-APAP.

At the same time, acetaminophen toxic lesion of protein-deficient animals is accompanied by weakening of detoxification potential of the liver. We have shown a decrease in p-hydroxylase and N-demethylase activity against the background of direct N-oxidation of drug xenobiotic, as evidenced by the growth of N-oxygenase activity. The decrease in CYP450 content under these experimental conditions is associated with an increase in the rate of its inactivation and transition to the inactive form, cytochrome P420.

It should be noted that the administration of toxic doses of acetaminophen is a key factor in the intensification of superoxide generation, regardless of the amount of protein in the diet.

Keywords:Cytochrome P450; P-Hydroxylation; N-Demethylation; N-Oxidation; Superoxide Anion Radical; Acetaminophen; Alimentary Protein Deficiency; Liver; Rats of Reproductive Age

References

1. Sinha S., et al. “Maternal protein malnutrition: current and future perspectives of spirulina supplementation in neuroprotection”. Frontiers in Neuroscience966 (2018): 1-18.
2. Ampong I., et al. “Dietary protein insufficiency: an important consideration in fatty liver disease?” British Journal of Nutrition6 (2020): 601-609.
3. Ciavarella C., et al. “Pharmacological (or synthetic) and nutritional agonists of PPAR-γ as candidates for cytokine storm modulation in COVID-19 disease”. Molecules 9 (2020): 1-15.
4. Iddir M., et al. “Strengthening the immune system and reducing inflammation and oxidative stress through diet and nutrition: considerations during the COVID-19 сrisis”. Nutrients 6 (2020): 1-39.
5. Amaral JF., et al. “Immunoglobulin production is impaired in protein-deprived mice and can be restored by dietary protein supplemntation”. Brazilian Journal of Medical and Biological Research 12 (2006): 1581-1586.
6. Antwi J., et al. “The nutrition-COVID-19 interplay: a review”. Current Nutrition Reports 4 (2021): 364-374.
7. Galmеs S., et al. “Current state of evidence: influence of nutritional and nutrigenetic factors on immunity in the COVID-19 pandemic framework”. Nutrients9 (2020): 1-33.
8. Skrajnowska D., et al. “Covid 19: diet composition and health”. Nutrients9 (2021): 1-21.
9. Katarey D. and Verma S. “Drug-induced liver injury”. Clinical Medicine (London, England) 6 (2016): s104-s109.
10. Jaeschke H., et al. “Novel therapeutic approaches against acetaminophen-induced liver injury and acute liver failure”. Toxicological Sciences: An Official Journal of the Society of Toxicology 2 (2020): 159-167.
11. Shader RI. “Acetaminophen (paracetamol), COVID-19, and misleading conclusions: a commentary”. Journal of Clinical Psychopharmacology2 (2021): 98-99.
12. Yang Y., et al. “Understanding a substrate’s product regioselectivity in a family of enzymes: a case study of acetaminophen binding in cytochrome P450s”. PLoS ONE2 (2014): e87058.
13. Radosavljeviс, et al. “The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis”. Medicinski Pregled 63.11-12 (2010): 827-832.
14. Guengerich FP. “Cytochrome P450 2E1 and its roles in disease”.
    Chemico-Biological Interactions322 (2020): 1-23.
15. Ghasemi A., et al. “The laboratory rat: age and body weight matter”. EXCLI Journal 20 (2021): 1431-1445.
16. 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.
17. Kopylchuk HP., et al. “Indexes of citrulline metabolism in rat liver under the toxic injury against the background of alimentary protein deficiency”. Ukrainian Biochemical Journal1 (2020): 113-119.
18. Marchenko МM., et al. “Activity of enzymatic detoxification systems in the mice liver under conditions of different retinoid provision”. The Ukrainian Biochemical Journal2 (2012): 42-47.
19. Shymanskyi IO., et al. “Liver cytochrome P450-hydroxylation system of tumor-bearing rats under the influence of ω-3 polyunsaturated fatty acids and vitamin D₃”. The Ukrainian Biochemical Journal 4 (2018): 36-44.
20. Kostenko VO., et al. “Production of superoxide anion radical and nitric oxide in renal tissues sutured with different surgical suture material”. Fiziolohichnyi Zhurnal 5 (2000): 56-62.
21. Mazaleuskaya LL., et al. “PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses”. Pharmacogenetics and Genomics8 (2015): 416-426.
22. Marto N., et al. “A simple method to measure sulfonation in man using paracetamol as probe drug”. Scientific Reports 11 (2021): 9036.
23. Kalsi SS., et al. “Does cytochrome P450 liver isoenzyme induction increase the risk of liver toxicity after paracetamol overdose?” Open Access Emergency Medicine 3 (2011): 69-76.
24. Yang Y., et al. “Understanding a substrate’s product regioselectivity in a family of enzymes: a case study of acetaminophen binding in cytochrome P450s”. PLoS ONE2 (2014): e87058.
25. Kopylchuk GP., et al. “The activity of glutathione synthesis and conjugation enzymes in rat hepatocytes under conditions of low-protein diet and acute liver injury”. Biology (Biological Systems)1 (2014): 10-15.
26. Gordeziani MSH., et al. “Monoxygenase and peroxidase mechanisms monoxygenase and peroxidase mechanisms peroxidase mechanisms of xenobiotic metabolism”. Annals of Agrarian Science 2 (2012): 1-13.
27. Bao Y., et al. “Acetaminophen-induced liver injury alters expression and activities of cytochrome P450 enzymes in an age-dependent manner in mouse liver”. Drug Metabolism and Disposition 5 (2020): 326-336.
28. Peng , et al. “RNA sequencing reveals dynamic changes of mRNA abundance of cytochromes P450 and their alternative transcripts during mouse liver development”. Drug Metabolism and Disposition 40.6 (2012): 1198-1209.
29. Johnson WW. et al. “Cytochrome p450 inactivation by pharmaceuticals and phytochemicals: therapeutic relevance”. Drug Metabolism Reviews 1 (2008): 101-147.
30. Veith A and Bhagavatula M. “Role of cytochrome P450s in the generation and metabolism of reactive oxygen species”. Current Opinion in Toxicology7 (2018): 44-51.
31. Peng CC., et al. “Cytochrome P450 2C9 type II binding studies on quinoline-4-carboxamide analogues”. Journal of Medicinal Chemistry24 (2008): 8000-8011.
32. Senge МО., et al. “Classic highlights in porphyrin and porphyrinoid total synthesis and biosynthesis”. Chemical Society Reviews 50 (2021): 4730-4789.
33. Zanger UM. and Schwab M. “Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation”. Pharmacology and Therapeutics1 (2013): 103-141.
34. Zhu BT. “On the general mechanism of selective induction of cytochrome P450 enzymes by chemicals: some theoretical considerations”. Expert Opinion on Drug Metabolism and Toxicology4 (2010): 483-494.
35. de Vries EM., et al. “Fasting-induced changes in hepatic P450 mediated drug metabolism are largely independent of the constitutive androstane receptor CAR”. PLoS ONE7 (2016): e0159552.
36. Kim SN., et al. “Induction of hepatic CYP2E1 by a subtoxic dose of acetaminophen in rats: increase in dichloromethane metabolism and carboxyhemoglobin elevation”. Drug Metabolism and Disposition 10 (2007): 1754-1758.
37. Santoh M., et al. “Acetaminophen induces accumulation of functional rat CYP3A via polyubiquitination dysfunction”. Scientific Reports21373 (2016): 1-10.
38. Kopylchuk GP., et al. “Oxidative modification of mitochondrial translation products in liver under the conditions of toxic hepatitis induced on the background of alimentary protein deficiency”. Bulletin of Problems Biology and Medicine 3 (120) (2015): 144-148.
39. Kaliman PA., et al. “Activity of 5-aminolevulinate synthase in the liver of rats under conditions of degradation of cytochrome P-450 with the introduction of cadmium chloride”. The Ukrainian Biochemical Journal 2 (2003): 99-102.
40. Zhang T., et al. “Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation”. Drug Metabolism Reviews 4. (2020): 501-530.
41. Cook DJ., et al. “Cytochromes P450. Advances in protein chemistry and structural biology”. Advances in Protein Chemistry and Structural Biology 105 (2016): 105-126.
42. Kopylchuk GP., et al. “Nitric oxide content in rats’ hepatocytes under conditions of alimentary protein deprivation and toxic injury”. Biology (Biological Systems)2 (2017): 159-165.
43.  

Citation

Citation: Нalyna Kopylchuk., et al. “Effect of Dietary Protein Deficiency on the Activity of Cytochrome P450 Enzyme Systems in the Liver of Rats of Reproductive Age Under Acetaminophen-Induced Injury”. Acta Scientific Gastrointestinal Disorders 5.4 (2022): 39-48.

Copyright

Copyright: © 2022 Нalyna Kopylchuk., et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.