Journal Technologies of Living Systems №2 for 2021 г.
Article in number:
Substantiation of the innocuous dosage of ribose in the absence of its influence on the level of pentoses and phosphopentoses in the liver
Type of article: scientific article
DOI: https://doi.org/10.18127/j20700997-202102-05
UDC: 577.124.25:616-092.9
Authors:

P.P. Zolin¹, V.D. Conway², E.A. Chigrinski³

1–3 Omsk State Medical University (Omsk, Russia)

2 Omsk State Agricultural University named after P.A. Stolypin (Omsk, Russia)     

Abstract:

D-(–)-ribose is a natural metabolite that is a part of various compounds of all living organisms. Presently much data has been obtained on the possibility of correction by exogenous ribose of a number of physiological and metabolic parameters of the organism, including extreme and terminal conditions of it. Ribose is used as a dietary supplement in sports nutrition; clinical trials of its pharmaceuticals are being conducted. Despite the high efficiency proved in numerous experiments, and the fact that ribose is a natural metabolite, it is not absolutely safe. The use of the ribose can be accompanied by various side effects, in our opinion the main of them are the temporary decrease in blood glucose level and the glycation (ribosylation) of the organism's biomolecules. However, these side effects are observed mainly with the insertion of high doses of ribose into the organism. Our previous studies have shown that a relatively low dose of ribose - 50 mg/kg body weight can have a beneficial effect on the physiological and biochemical parameters of the organism even with a single injection. However, it is still questionable that levels of pentoses and their phosphorylated derivatives in internal organs and tissues, after the administration of exogenous ribose. Since data on non-enzymatic glycation of biomolecules not only by ribose but also by its derivatives have recently appeared in the literature, the question of measuring the levels of pentoses in tissues after the administration of exogenous ribose to healthy animals and subjected to various influences becomes topical. The aim of this work is to check the safety of a single administration of ribose at a dose of 50 mg/kg to healthy and resuscitated rats by the criterion of increasing levels of pentose-containing substances in the liver. The absence of an increase in these substances does not imply damage to the biomolecules of the organism by the ribose and its metabolites.

The experiments were conducted on 59 non-inbred white male rats. To simulate clinical death, 34 rats were intubated under ether anesthesia, then the endotracheal tube was closed for 6.5 minutes, after that the animals were resuscitated by artificial respiration and indirect heart massage. 21 successfully resuscitated rats were divided into groups “Resuscitation” and “Resuscitation+Ribose”. The remaining 25 rats were subjected to control influences (anesthesia, fixation, intubation) and were divided into the “Control” and “Ribose” groups. The abdominal cavities of animals of all 4 groups in 30 minutes after resuscitation or control influences under ether anesthesia were opened and their livers were intravitally frozen in liquid nitrogen. 25 minutes before euthanasia, all rats were injected with a 0.9% sodium chloride solution in a volume of 2.5 ml/kg body weight into the femoral vein. The solution administered to animals from the “Ribose” and “Resuscitation+Ribose” groups contained D-ribose at a dose of 50 mg/kg body weight. The concentrations of total pentoses, phosphopentoses and non-phosphorylated pentoses were measured in the hydrochloric acid extract of the liver.

It was found that 30 minutes after resuscitation, the content of phosphopentosis in the group “Resuscitation” is reduced by 10% compared with the “Control” group, and the total content of pentoses is reduced by 11%, however, these differences between the groups are not statistically significant. This may indicate a slight decrease in pentose-5-phosphates through the pentose cycle. Intravenous administration of the ribose in the studied dose to healthy animals also did not significantly affect the concentration of the studied fractions of pentoses. The administration of ribose to rats immediately after resuscitation led to a decrease in the group of “Resuscitation+Ribose” compared to the “Control” group: total pentoses by 13%, phosphopentosis by 10%, non-phosphorylated pentoses by 20%. But these differences were also not statistically significant.

Thus, the experiment showed that a single injection of ribose at a dose of 50 mg/kg of body weight to healthy and resuscitated rats does not cause statistically significant changes in the content of total pentoses, phosphopentoses and non-phosphorylated pentoses in the liver. It means that this amount of exogenous ribose is metabolized very quickly. The absence of the elevated level of pentoses of various fractions in the liver, the organ that is the main consumer of exogenous ribose, confirms our assumption that this dosage of ribose is innocuous and not capable of causing pathological ribosylation of cellular biomolecules. The obtained result is especially relevant in the context of the discussion of ribose safety in the scientific literature.

Pages: 39-46
For citation

Zolin P.P., Conway V.D., Chigrinski E.A. Substantiation of the innocuous dosage of ribose in the absence of its influence on the level of pentoses and phosphopentoses in the liver. Technologies of Living Systems. 2021. V. 18. № 2. Р. 39–46. DOI: https://doi.org/10.18127/j20700997-202102-05 (in Russian)

References
  1. Shecterle L.M., Terry K.R., St. Cyr J.A. Potential clinical benefits of D-ribose in ischemic cardiovascular disease. Cureus. 2018. V. 10 (3). P. E2291.
  2. Bayram M., St. Cyr J.A., Abraham W.T. D-ribose aids heart failure patients with preserved ejection fraction and diastolic dysfunction: a pilot study. Ther. Adv. Cardiovasc. Dis. 2015. V. 9 (3). P. 56–65.
  3. Mahoney D.E., Hiebert J.B., Thimmesch A., Pierce J.T., Vacek J.L., Clancy R.L., Sauer A.J., Pierce J.D. Understanding D-ribose and mitochondrial function. Adv. Biosci. Clin. Med. 2018. V. 6 (1). P. 1–5.
  4. Pierce J.D., Mahoney D.E., Hiebert J.B., Thimmesch A.R., Diaz F.J., Smith C., Shen Q., Mudaranthakam D.P., Clancy R.L. Study protocol, randomized controlled trial: reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D-ribose. BMC Cardiovasc. Disord. 2018. V. 18 (1). P. 57.
  5. Zolin P.P., Konvay V.D. Vliyaniye ribozy na urovni mononukleotidov v pecheni v rannem postreanimatsionnom periode. Dalnevostochnyy meditsinskiy zhurnal. 2017. № 4. S. 78–81 (in Russian).
  6. Zolin P.P., Lebedev V.M., Konvay V.D. Matematicheskoye modelirovaniye biokhimicheskikh protsessov s primeneniyem regressionnogo analiza: Monografiya. Omsk: Izd-vo Omskogo gos. un-ta. 2009. 344 s. (in Russian).
  7. Kerksick C.M., Wilborn C.D., Roberts M.D., Smith-Ryan A., Kleiner S.M., Jäger R., Collins R., Cooke M., Davis J.N., Galvan E., Greenwood M., Lowery L.M., Wildman R., Antonio J., Kreider R.B. ISSN exercise & sports nutrition review update: research & recommendations. J. Int. Soc. Sports Nutr. 2018. V. 15. P. 38.
  8. Seifert J.G., Brumet A., St Cyr J.A. The influence of d-ribose ingestion and fitness level on performance and recovery. J. Int. Soc. Sports Nutr. 2017. V. 14. P. 47.
  9. Bayram M., Perkowski D., St. Cyr J.A., Abraham W.T. Clinical significance and applications of D-ribose in cardiovascular disease. Int. Arch. Cardiovasc. Dis. 2018. V. 2 (2:013). P. 1–9.
  10. Turck D., Bresson J.‐L., Burlingame B., Dean T., Fairweather-Tait S., Heinonen M., Hirsch-Ernst K.I., Mangelsdorf I., McArdle H.J., Naska A., Neuhäuser‐Berthold M., Nowicka G., Pentieva K., Sanz Y., Siani A., Sjödin A., Stern M., Tomé D., Vinceti M., Willatts P., Engel K.-H., Marchelli R., Poting A., Poulsen M., Schlatter J.R., Germini A., van Loveren H. Safety of D‐ribose as a novel food pursuant to regulation (EU) 2015/2283. EFSA Journal. 2018. V. 16 (5). P. Е5265.
  11. Gross M., Zöllner N. Serum levels of glucose, insulin, and C-peptide during long-term D-ribose administration in man. Klin. Wochenschr. 1991. V. 69 (1). P. 31–36.
  12. Chen X., Su T., Chen Y., He Y., Liu Y., Xu Y., Wei Y., Li J., He R. D-Ribose as a contributor to glycated haemoglobin. EBioMedicine. 2017. V. 25. P. 143–153.
  13. Yu L., Chen Y., Xu Y., He T., Wei Y., He R. D-ribose is elevated in T1DM patients and can be involved in the onset of encephalopathy. Aging. 2019. V. 11 (14). P. 4943–4969.
  14. Hong J., Li G., Zhang Q., Ritter J., Li W., Li P.-L. D-ribose induces podocyte NLRP3 inflammasome activation and glomerular injury via AGEs/RAGE pathway. Front. Cell Dev. Biol. 2019. V. 7. P. 259.
  15. Chen Y., Yu L., Wang Y., Wei Y., Xu Y., He T., He R. D-ribose contributes to the glycation of serum protein. Biochim. Biophys. Acta Mol. Basis Dis. 2019. V. 1865 (9). P. 2285–2292.
  16. Waris S., Pischetsrieder M., Saleemuddin M. DNA damage by ribose: inhibition at high ribose concentrations. Indian J. Biochem. Biophys. 2010. V. 47 (3). P. 148–156.
  17. Akhter F., Khan M.S., Ahmad S. Acquired immunogenicity of calf thymus DNA and LDL modified by D-ribose: a comparative study. Int. J. Biol. Macromol. 2015. V. 72. P. 1222–1227.
  18. Akhter F., Khan M.S., Alatar A.A., Faisal M., Ahmad S. Antigenic role of the adaptive immune response to D-ribose glycated LDL in diabetes, atherosclerosis and diabetes atherosclerotic patients. Life Sci. 2016. V. 151. P. 139–146.
  19. Bailey A.J., Sims T.J., Avery N.C., Halligan E.P. Non-enzymic glycation of fibrous collagen: Reaction products of glucose and ribose. Biochem. J. 1995. V. 305 (Pt 2). P. 385–390.
  20. Valencia J.V., Weldon S.C., Quinn D., Kiers G.H., DeGroot J., TeKoppele J.M., Hughes T.E. Advanced glycation end product ligands for the receptor for advanced glycation end products: Biochemical characterization and formation kinetics. Anal. Biochem. 2004. V. 324 (1). P. 68–78.
  21. Wei Y., Chen L., Chen J., Ge L., He R.Q. Rapid glycation with D-ribose induces globular amyloid-like aggregations of BSA with high cytotoxicity to SH-SY5Y cells. BMC Cell Biology. 2009. V. 10. P. 10.
  22. Sell D.R., Monnier V.M. Structure elucidation of a senescence cross-link from human extracellular matrix. Implication of pentoses in the aging process. J. Biol. Chem. 1989. V. 264 (36). P. 21597–21602.
  23. Clark P.M., Flores G., Evdokimov N.M., McCracken M.N., Chai T., Nair-Gill E., O’Mahony F., Beaven S.W., Faull K.F., Phelps M.E., Jung M.E., Witte O.N. Positron emission tomography probe demonstrates a striking concentration of ribose salvage in the liver. Proc. Natl. Acad. Sci. USA. 2014. V. 111 (28). P. E2866–E2874.
  24. Zimmer H.-G., Gerlach E. Stimulation of myocardial adenine nucleotide biosynthesis by pentoses and pentitols. Pflugers Arch. 1978.  V. 376 (3). P. 223–227.
  25. Sergiyenko V.I., Bondareva I.B. Matematicheskaya statistika v klinicheskikh issledovaniyakh. M.: GEOTAR-Media. 2006. 304 s. (In Russian).
  26. Konvay V.D. Narusheniye purinovogo obmena v pecheni v postreanimatsionnom periode i ego profilaktika: Avtoref. diss. ... dokt. med. nauk. Tomsk. 1988. 38 s. (in Russian).
  27. Zolin P.P., Konvay V.D. Metod izucheniya obmena pentoz pri gipoksicheskikh sostoyaniyakh. Omsk: Omskiy meditsinskiy institut. 1991. 19 s. Dep. v VINITI № 4705-V91. Referativnyy zhurnal «Biokhimiya». 1992. № 6. S. 45 (in Russian).
  28. Ishiwata K., Kuzuya N., Kajinuma H., Tsushima T., Irie M., Hetenyi G.Jr. Sustained hypoglycemia in response to intravenous infusion of D-ribose in normal dogs. Endocrinol. Jap. 1978. V. 25 (2). P. 163–169.
  29. Gross M., Reiter S., Zollner N. Metabolism of D-ribose administered continuously to healthy persons and to patients with myoadenylate deaminase deficiency. Klin. Wochenschr. 1989. V. 67. P. 1205–1213.
  30. Alzoubi K.H., Ismail Z.B., Al-Essa M.K., Alshogran O.Y., Abutayeh R.F., Abu-Baker N. Pharmacokinetic evaluation of D-ribose after oral and intravenous administration to healthy rabbits. Clin. Pharmacol. 2018. V.10. P. 73–78.
Date of receipt: 05.02.2020
Approved after review: 15.12.2020
Accepted for publication: 19.01.2021