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. 2022 Oct 29;27(21):7359.
doi: 10.3390/molecules27217359.

Structural Investigation of Betulinic Acid Plasma Metabolites by Tandem Mass Spectrometry

Roxana Ghiulai  1   2 , Marius Mioc  2   3 , Roxana Racoviceanu  2   3 , Alexandra Prodea  2   3 , Andreea Milan  2   3 , Dorina Coricovac  2   4 , Cristina Dehelean  2   4 , Ștefana Avram  2   5 , Alina D Zamfir  6   7 , Cristian V A Munteanu  8 , Viviana Ivan  9 , Codruța Şoica  1   2
Affiliations

Structural Investigation of Betulinic Acid Plasma Metabolites by Tandem Mass Spectrometry

Roxana Ghiulai et al. Molecules. .

Abstract

Betulinic acid (BA) has been extensively studied in recent years mainly for its antiproliferative and antitumor effect in various types of cancers. Limited data are available regarding the pharmacokinetic profile of BA, particularly its metabolic transformation in vivo. In this study, we present the screening and structural investigations by ESI Orbitrap MS in the negative ion mode and CID MS/MS of phase I and phase II metabolites detected in mouse plasma after the intraperitoneal administration of a nanoemulsion containing BA in SKH 1 female mice. Obtained results indicate that the main phase I metabolic reactions that BA undergoes are monohydroxylation, dihydroxylation, oxidation and hydrogenation, while phase II reactions involved sulfation, glucuronidation and methylation. The fragmentation pathway for BA and its plasma metabolites were elucidated by sequencing of the precursor ions by CID MS MS experiments.

Keywords: ESI CID MS/MS; betulinic acid; phase I metabolites; phase II metabolites.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of betulinic acid (BA) (3β, hydroxy-lup-20(29)-en-28-oic acid).
Figure 2
Figure 2
Structural characterization of betulinic acid (BA) (3β, hydroxy-lup-20(29)-en-28-oic acid). (A) ESI CID MS/MS spectra of the [M-H]− ion detected at m/z 455.35 in the negative ion mode: spray voltage 0.70 kV, capillary temperature 275 °C and collision energies within 0–35 eV. (B) Proposed fragmentation pathway.
Figure 3
Figure 3
ESI CID MS/MS spectra in the negative ion mode of phase I metabolites detected as [M-H]− ions: M1 (m/z 457.37), M2 (m/z 471.35), M3 (m/z 485.33) and M4 (m/z 487.34); spray voltage 0.70 kV, capillary temperature 275 °C and collision energies within 0–35 eV.
Figure 4
Figure 4
Proposed fragmentation pathway for phase I metabolites: M1–M2.
Figure 5
Figure 5
Proposed fragmentation pathway for phase I metabolites: M3–M4.
Figure 6
Figure 6
ESI CID MS/MS spectra in the negative ion mode of phase II metabolites detected as [M-H]− ions: M5 (m/z 469.37), M6 (m/z 535.31), M7 (m/z 551.30), M8 (m/z 565.28), M9 (m/z 567.30), M10 (m/z 631.39), M11 (m/z 647.38), M12 (m/z 661.36) and M13 (m/z 663.37); spray voltage 0.70 kV, capillary temperature 275 °C and collision energies within 0–35 eV.
Figure 7
Figure 7
Proposed fragmentation pathway for phase II metabolites: M6–M7.
Figure 8
Figure 8
Proposed fragmentation pathway for phase II metabolites: M8–M9.
Figure 9
Figure 9
Proposed fragmentation pathway for phase II metabolites: M10–M11.
Figure 10
Figure 10
Proposed fragmentation pathway for phase II metabolites: M12–M13.
Figure 11
Figure 11
Proposed metabolic pathway for betulinic acid (BA) (3β, hydroxy-lup-20(29)-en-28-oic acid) in SKH1 female mice.
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References

    1. Fulda S. Betulinic acid for cancer treatment and prevention. Int. J. Mol. Sci. 2008;9:1096–1107. doi: 10.3390/ijms9061096. - DOI - PMC - PubMed
    1. Guo S., Duan J.A., Tang Y.P., Yang N.Y., Qian D.W., Su S.L., Shang E.X. Characterization of triterpenic acids in fruits of ziziphus species by HPLC-ELSD-MS. J. Agric. Food Chem. 2010;58:6285–6289. doi: 10.1021/jf101022p. - DOI - PubMed
    1. Karan B.N., Maity T.K., Pal B.C., Singha T., Jana S. Betulinic Acid, the first lupane-type triterpenoid isolated via bioactivity-guided fractionation, and identified by spectroscopic analysis from leaves of Nyctanthes arbor-tristis: Its potential biological activities in vitro assays. Nat. Prod. Res. 2019;33:3287–3292. doi: 10.1080/14786419.2018.1470171. - DOI - PubMed
    1. Mioc M., Prodea A., Racoviceanu R., Mioc A., Ghiulai R., Milan A., Voicu M., Mardale G., Șoica C. Recent Advances Regarding the Molecular Mechanisms of Triterpenic Acids: A Review (Part II) Int. J. Mol. Sci. 2022;23:8896. doi: 10.3390/ijms23168896. - DOI - PMC - PubMed
    1. Hordyjewska A., Ostapiuk A., Horecka A., Kurzepa J. Betulin and betulinic acid: Triterpenoids derivatives with a powerful biological potential. Phytochem. Rev. 2019;18:929–951. doi: 10.1007/s11101-019-09623-1. - DOI

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