LUPANE TRITERPENOIDS AS MODULATORS OF FUNCTIONAL ACTIVITY OF RAT LIVER MITOCHONDRIA
Abstract and keywords
Abstract (English):
The effect of plant triterpenoid betulin and its derivative betulonic acid on rat mitochondria is considered. It was found that betulonic acid and, to a lesser extent, betulin activate mitochondrial respiration in states 2 and 4 and inhibit respiration stimulated by ADP and DNP. In this case, the effect of betulonic acid leads to a significant decrease in respiratory control and the ADP/O coefficient, as well as to a decrease in membrane potential. The effects of both compounds were most pronounced when succinate was used as a respiratory substrate. It was established that the effect of these agents on the functional parameters of organelles is due to both the protonophore effect of betulonic acid and the inhibition of respiratory chain complexes by both compounds. Both agents also significantly enhanced the generation of H2O2 in succinate oxidizing mitochondria, while betulonic acid exerted an antioxidant effect in the presence of NAD-dependent substrates. It was also found that betulin induces mitochondrial aggregation. Betulonic acid was much less effective in this case. Possible mechanisms of the effect of betulin and betulonic acid on the functioning of rat liver mitochondria are discussed.

Keywords:
betulin, betulonic acid, mitochondria, inhibition, aggregation
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References

1. Connolly J.D., Hill R.A. Triterpenoids. Nat. Prod. Rep., 2017, no. 27, pp. 79-132. DOI: 10.1039/b808530g.

2. Kreiter J., Rupprecht A., Zimmermann L., Moschinger M., Rokitskaya T.I., Antonenko Y.N., Gille L., Fedorova M., Pohl E.E. Molecular mechanisms responsible for pharmacological effects of genipin on mitochondrial proteins. Biophys. J., 2019, vol. 117, no. 10, pp. 1845-1857. DOI: 10.1016/j.bpj.2019.10.021.

3. Matsuda H., Ishikado A., Nishida N., Ninomiya K., Fujiwara H., Kobayashi Y., Yoshikawa M. Hepatoprotective, superoxide scavenging, and antioxidative activities of aromatic constituents from the bark of Betula platyphylla var. japonica. Bioorg. Med. Chem. Lett., 1998, vol. 8, no. 21, pp. 2939-2944. DOI: 10.1016/S0960-894X(98)00528-9.

4. Tolstikova T.G., Sorokina I.V., Tolstikov G.A., Tolstikov A.G., Flekhter O.B. Biological activity and pharmacological prospects of lupane terpenoids: I. natural lupane derivatives. Russ. J. Bioorg. Chem., 2006, no. 32, pp. 37-49. DOI: 10.1134/S1068162006010031.

5. Król S.K., Kiełbus M., Rivero-Müller A., Stepulak A. Comprehensive review on betulin as a potent anticancer agent. Biomed. Res. Int., 2015, 584189. DOI: 10.1155/2015/584189

6. Yang S., Zhao Q., Xiang H., Liu M., Zhang Q., Xue W., Song B., Yang S. Antiproliferative activity and apoptosis-inducing mechanism of constituents from Toona sinensis on human cancer cells. Cancer. Cell Int., 2013, vol. 13, no. 1, p. 12. DOI: 10.1186/1475-2867-13-12.

7. Cháirez-Ramírez M.H., Moreno-Jiménez M.R., González-Laredo R.F., Gallegos-Infante J.A., Rocha-Guzmán N.E. Lupane-type triterpenes and their anti-cancer activities against most common malignant tumors: A review. EXCLI. J., 2016, no. 15, pp. 758-771. DOI: 10.17179/excli2016-642.

8. Leong K.H., Mahdzir M.A., Din M.F., Awang K., Tanaka Y., Kulkeaw K., Ishitani T., Sugiyama D. Induction of intrinsic apoptosis in leukaemia stem cells and in vivo zebrafish model by betulonic acid isolated from Walsura pinnata Hassk (Meliaceae). Phytomedicine, 2017, no. 26, pp. 11-21. DOI: 10.1016/j.phymed.2016.12.018.

9. Belosludtsev K.N., Dubinin M.V., Belosludtseva N.V., Mironova G.D. Mitochondrial Ca2+ transport: mechanisms, molecular structures, and role in cells. Biochemistry, 2019, vol. 84, no. 6, pp. 593-607. DOI: 10.1134/S0006297919060026.

10. Dubinin M.V., Samartsev V.N., Stepanova A.E., Khoroshavina E.I., Penkov N.V., Yashin V.A., Starinets V.S., Mikheeva I.B., Gudkov S.V., Belosludtsev K.N. Membranotropic effects of ω-hydroxypalmitic acid and Ca2+ on rat liver mitochondria and lecithin liposomes. Aggregation and membrane permeabilization. J. Bioenerg. Biomembr., 2018, vol. 50, no. 5, pp. 391-401. DOI: 10.1007/s10863-018-9771-y.

11. Fulda S. Betulinic acid: a natural product with anticancer activity. Mol. Nutr. Food Res., 2019, vol. 53, no. 1, pp. 140-146. DOI: 10.1002/mnfr.200700491.

12. Li Y., He K., Huang Y., Zheng D., Gao C., Cui L., Jin Y.H. Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells. Mol. Carcinog., 2010, vol. 49, no. 7, pp. 630-640. DOI: 10.1002/mc.20638.

13. Belosludtsev K.N., Belosludtseva N.V., Agafonov A.V., Pavlik L.L., Tenkov K.S., Samartsev V.N., Dubinin M.V., Penkov N.V., Yashin V.A. Study of the mechanism of permeabilization of lecithin liposomes and rat liver mitochondria by the antimicrobial drug triclosan. Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018, vol. 1860, no. 2, pp. 246-271. DOI: 10.1016/j.bbamem.2017.09.018.

14. Chance B., Williams G.R. Respiratory enzymes in oxidative phosphorylation. I. Kinetics of oxygen utilization. J. Biol. Chem., 1955, vol. 217, no. 1, pp. 383-393.

15. Hwang B.Y., Chai H.B., Kardono L.B., Riswan S., Farnsworth N.R., Cordell G.A., Pezzuto J.M., Kinghorn A.D. Cytotoxic triterpenes from the twigs of Celtis philippinensis, Phytochemistry, 2003, vol. 62, no. 2, pp. 197-201. DOI: 10.1016/s0031-9422(02)00520-4.


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