3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation

doi:10.1007/s13659-024-00442-2

Natural Products and Bioprospecting ›› 2024, Vol. 14 ›› Issue (2): 7-7.DOI: 10.1007/s13659-024-00442-2

• ORIGINAL ARTICLES • Previous Articles

3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation

Li-Jun Ruan^1,2, Zhi-Jun Song², Ren-Wang Jiang¹

1. State Key Laboratory of Bioactive Molecules and Draggability Assessment, College of Pharmacy, Jinan University, Guangzhou, 510632, China;
2. National Engineering Research Center for Southwest Endangered Medicinal Materials Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, China

Received:2023-12-01 Online:2024-05-16 Published:2024-04-24
Contact: Ren-Wang Jiang,E-mail:trwjiang@jnu.edu.cn
Supported by:
This work was financially supported by Guangxi Natural Science Foundation Program (Grant Number 2021GXNSFBA220068), National Natural Science Foundation of China (Grant Number 81872760 and 82204975), Natural Science Foundation of Guangdong province (Grant Number 2021A1515011251), Guangdong scientific scheme (Grant Number 2021A0505030032).

3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation

Li-Jun Ruan^1,2, Zhi-Jun Song², Ren-Wang Jiang¹

1. State Key Laboratory of Bioactive Molecules and Draggability Assessment, College of Pharmacy, Jinan University, Guangzhou, 510632, China;
2. National Engineering Research Center for Southwest Endangered Medicinal Materials Resources Development, Guangxi Botanical Garden of Medicinal Plants, Nanning, 530023, China

通讯作者: Ren-Wang Jiang,E-mail:trwjiang@jnu.edu.cn
基金资助:
This work was financially supported by Guangxi Natural Science Foundation Program (Grant Number 2021GXNSFBA220068), National Natural Science Foundation of China (Grant Number 81872760 and 82204975), Natural Science Foundation of Guangdong province (Grant Number 2021A1515011251), Guangdong scientific scheme (Grant Number 2021A0505030032).

Abstract

Abstract: Bufadienolides, naturally occurring steroids primarily found in toads, have garnered attention for their pharmacological properties and ecological significance. In this study, we isolated and identified 21 bufadienolides from the gallbladders of Bufo gargarizans, comprising four new compounds and 17 known ones. Notably, the predominance of 15 bufadienolides with a 3α-OH configuration in toad bile differs significantly from the 3β-OH bufadienolides found in venom secreted by toad glands. Moreover, our investigation into the biotransformation of 3β-OH and 3α-OH bufadienolides in the liver and kidney tissues of toads revealed an irreversible conversion from 3β-OH to 3α-OH bufadienolides, suggesting a crucial role in toad self-detoxification. These findings provide valuable insights into the structural diversity of bufadienolides and advance our understanding of their medical and ecological significance.

Key words: Bufadienolides, Bufo gargarizans, Toad bile, Self-defense, Biotransformation

摘要： Bufadienolides, naturally occurring steroids primarily found in toads, have garnered attention for their pharmacological properties and ecological significance. In this study, we isolated and identified 21 bufadienolides from the gallbladders of Bufo gargarizans, comprising four new compounds and 17 known ones. Notably, the predominance of 15 bufadienolides with a 3α-OH configuration in toad bile differs significantly from the 3β-OH bufadienolides found in venom secreted by toad glands. Moreover, our investigation into the biotransformation of 3β-OH and 3α-OH bufadienolides in the liver and kidney tissues of toads revealed an irreversible conversion from 3β-OH to 3α-OH bufadienolides, suggesting a crucial role in toad self-detoxification. These findings provide valuable insights into the structural diversity of bufadienolides and advance our understanding of their medical and ecological significance.

关键词: Bufadienolides, Bufo gargarizans, Toad bile, Self-defense, Biotransformation

Li-Jun Ruan, Zhi-Jun Song, Ren-Wang Jiang. 3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation[J]. Natural Products and Bioprospecting, 2024, 14(2): 7-7.

Li-Jun Ruan, Zhi-Jun Song, Ren-Wang Jiang. 3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation[J]. 应用天然产物, 2024, 14(2): 7-7.

References

[1] Zhan X, Wu H, Wu H, Wang R, Luo C, Gao B, Chen Z, Li Q. Metabolites from Bufo gargarizans (Cantor, 1842): a review of traditional uses, pharmacological activity, toxicity and quality control. J Ethnopharmacol. 2020;246: 112178.
[2] Kolodziejczyk-Czepas J, Stochmal A. Bufadienolides of Kalanchoe species: an overview of chemical structure, biological activity and prospects for pharmacological use. Phytochem Rev. 2017;16:1155-71.
[3] Steyn PS, van Heerden FR. Bufadienolides of plant and animal origin. Nat Prod Rep. 1998;15:397-413.
[4] Li FJ, Hu JH, Ren X, Zhou CM, Liu Q, Zhang YQ. Toad venom: a comprehensive review of chemical constituents, anticancer activities, and mechanisms. Arch Pharm. 2021;354: e2100060.
[5] Li BJ, Tian HY, Zhang DM, Lei YH, Wang L, Jiang RW, Ye WC. Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans. Fitoterapia. 2015;105:7-15.
[6] Rodriguez C, Ibáñez R, Mojica L, Ng M, Spadafora C, Durant-Archibold AA, Gutiérrez M. Bufadienolides from the skin secretions of the neotropical toad Rhinella alata (Anura: Bufonidae): antiprotozoal activity against Trypanosoma cruzi. Molecules. 2021;26:4217.
[7] Lee SS, Derguini F, Bruening RC, Nakanishi K, Wallick ET, Akizawa T, Rosenbaum CS, Butler VP. Digitalis-like compounds of toad bile: sulfation and reduction of bufadienolides decrease potency of Na, K-ATPase inhibition. Heterocycles. 1994;39:669-86.
[8] Matsukawa M, Akizawa T, Mukai T, Yoshioka M, Morris JF, Butler VP. Structures and biological activities of bufadienolides from the toad, Bufo marinus. Symp Chem Nat Prod. 1994;36:807-14.
[9] Flier JS, Maratos-Flier E, Pallotta JA, McIsaac D. Endogenous digitalis-like activity in the plasma of the toad Bufo marinus. Nature. 1979;279:341-3.
[10] Lichtstein D, Kachalsky S, Deutsch J. Identification of a ouabain-like compound in toad skin and plasma as a bufodienolide derivative. Life Sci. 1986;38:1261-70.
[11] Lichtstein D, Gati I, Haver E, Katz U. Digitalis-like compounds in the toad Bufo viridis: tissue and plasma levels and significance in osmotic stress. Life Sci. 1992;51:119-28.
[12] Matsukawa M, Mukai T, Akizawa T, Miyatake S, Yoshioka M, Morris J, Butler P. Isolation and characterization of novel endogenous digitalis-like factors in the ovary of the giant toad, Bufo marinus. J Nat Prod. 1998;61:1476-81.
[13] Zhou SW, Quan JY, Li ZW, Ye G, Shang Z, Chen ZP, Wang L, Li XY, Zhang XQ, Li J, Liu JS, Tian HY. Bufadienolides from the eggs of the toad Bufo bufo gargarizans and their antimelanoma activities. J Nat Prod. 2021;84:1425-33.
[14] Zhang PW, Tian HY, Nie QL, Wang L, Zhou SW, Ye WC, Zhang DM, Jiang RW. Structures and inhibitory activity against breast cancer cells of new bufadienolides from the eggs of toad Bufo bufo gargarizans. RSC Adv. 2016;6:93832-41.
[15] Tang HJ, Ruan LJ, Tian HY, Liang GP, Ye WC, Hughes E, Esmann M, Fedosova NU, Chung TY, Tzen JT, Jiang RW, Middleton DA. Novel stereoselective bufadienolides reveal new insights into the requirements for Na⁺, K⁺-ATPase inhibition by cardiotonic steroids. Sci Rep. 2016;6:29155.
[16] Lichtstein D, Gati I, Ovadia H. Digitalis-like compounds in the toad Bufo viridis: interactions with plasma proteins. J Cardiovasc Pharmacol. 1993;22:S102-5.
[17] Ruan LJ, Chen HY, Xu W, Song ZJ, Jiang RW. Structures and biological activities of new bile acids from the gallbladder of Bufo bufo gargarizans. Molecules. 2022;27:7671.
[18] Tian HY, Ruan LJ, Yu T, Zheng QF, Chen NH, Wu RB, Zhang XQ, Wang L, Jiang RW, Ye WC. Bufospirostenin A and Bufogargarizin C, steroids with rearranged skeletons from the toad Bufo bufo gargarizans. J Nat Prod. 2017;80:1182-6.
[19] Tian HY, Wang L, Zhang XQ, Zhang DM, Wang Y, Liu JS, Jiang RW, Ye WC. New bufadienolides and C(23) steroids from the venom of Bufo bufo gargarizans. Steroids. 2010;75(12):884-90.
[20] Cao XT, Wang D, Wang N, Dai YH, Cui Z. Isolation and identification of bufogenin constituents from the skin of Bufo bufo gargarizans Cantor. J Shenyang Pharm Univ. 2009;26:778-81.
[21] Kamano Y, Nogawa TA, Hayashi M, Inoue M, Drasar P. Isolation and structure of a 20,21-epoxybufenolide series from “Ch’an Su.” J Nat Prod. 2002;65:1001-5.
[22] Ma XC, Cui J, Zheng J, Guo DA. Microbial transformation of three bufadienolides by Penicillium aurantigriseum and its application for metabolite identification in rat. J Mol Catal B Enzymatic. 2007;48:42-50.
[23] Han LY, Si N, Liu JQ, Zhao HY, Yang J, Bian BL, Wang HJ. Chemical consituents of bufadienolides in cinobufacino injection. Acta Pharm Sin. 2014;49:1574-7.
[24] Ye M, Qu G, Guo H, Guo D. Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure-activity relationships. J Steroid Biochem Mol Biol. 2004;91:87-98.
[25] Zhang X, Ye M, Dong YH, Hu HB, Tao SJ, Yin J, Guo DA. Biotransformation of bufadienolides by cell suspension cultures of Saussurea involucrata. Phytochemistry. 2011;72:1779-85.
[26] Ye M, Han J, An D, Tu G, Guo D. New cytotoxic bufadienolides from the biotransformation of resibufogenin by Mucor polymorphosporus. Tetrahedron. 2005;61:8947-55.
[27] Tempone AG, Pimenta DC, Lebrun I, Sartorelli P, Taniwaki NN, Andrade HFD, Antoniazzi MM, Jared C. Antileishmanial and antitrypanosomal activity of bufadienolides isolated from the toad Rhinella jimi parotoid macrogland secretion. Toxicon. 2008;52:13-21.
[28] Shimada K, Ishii N, Nambara T. Occurrence of bufadienolides in the skin of Bufo viridis Laur. Chem Pharm Bull. 1986;34:3454-7.
[29] Li X, Guo Z, Wang C, Shen A, Liu Y, Zhang X, Zhao W, Liang X. Purification of bufadienolides from the skin of Bufo bufo gargarizans Cantor with positively charged C18 column. J Pharm Biomed Anal. 2014;92:105-13.
[30] Verhoeven CHJ, Vos RME, Delbressine LPC. The in vivo metabolism of tibolone in animal species. Eur J Drug Metab Pharmacokinet. 2002;27:1-10.
[31] Huang XF, Luu-The V. Molecular characterization of a first human 3(α→β)-hydroxysteroid epimerase. J Biol Chem. 2000;275:29452-7.
[32] Shimada K, Miyashiro Y, Nishio T. Characterization of in vitro metabolites of toad venom using high-performance liquid chromatography and liquid chromatography-mass spectrometry. Biomed Chromatogr. 2006;20:1321-7.
[33] Hutchinson D, Mori A, Savitzky A, Burghardt G, Wu X, Meinwald J, Schroeder F. Dietary sequestration of defensive steroids in nuchal glands of the Asian snake Rhabdophis tigrinus. Proc Natl Acad Sci USA. 2007;104:2265-70.
[34] Qin SQ, Xu W, Wang QQ, Chen RY, Yang DZ, Lu Y, Ye WC, Jiang RW. A box-in-box supramolecular assembly for the highly selective recognition of natural, epigenetically and chemically modified cytosines in water. Org Chem Front. 2024;11:194-204.

3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation

3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 1

Recommended Articles

Metrics

Comments