Resibufogenin

The glandular body of Bufo bufo gargarizans Cantor

Resibufogenin, a component of huachansu, has been shown to exhibit the anti-proliferative effect against cancer cells, and this may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3β. IC50 Value: Target: In vitro: The effects of Resibufogenin on the outward delayed rectifier potassium current (IK) and outward transient potassium current (IA) in rat hippocampal neurons was investigated, and it inhibited both IK and IA, at 1 μM concentration RBG could alter some channel kinetics and gating properties of IK, such as steady-state activation and inactivation curves, open probability and time constants [1]. In vivo: Resibufogenin prevented evidence of oxidative stress in preeclamptic rats [2].

References:
[1]. Hao S, et al. Effects of Resibufogenin and Cinobufagin on voltage-gated potassium channels in primary cultures of rat hippocampal neurons. Toxicol In Vitro. 2011 Dec 25(8):1644-53. [2]. Uddin MN, et al. Resibufogenin administration prevents oxidative stress in a rat model of human preeclampsia. Hypertens Pregnancy. 2012 31(1):70-8. [3]. Ichikawa M, et al. Resibufogenin Induces G1-Phase Arrest through the Proteasomal Degradation of Cyclin D1 in Human Malignant Tumor Cells. PLoS One. 2015 Jun 29 10(6):e0129851. [4]. Hao S, et al. Effects of resibufogenin on voltage-gated sodium channels in cultured rat hippocampal neurons. Neurosci Lett. 2011 Aug 26 501(2):112-6. [5]. Zheng J, et al. Novel microbial transformation of resibufogenin by Absidia coerules. Nat Prod Commun. 2011 Nov 6(11):1581-4. [6]. Xin XL, et al. Novel microbial transformation of resibufogenin by Fusarium solani. J Asian Nat Prod Res. 2011 Sep 13(9):831-7.

Isolation and identification of phase I metabolites of resibufogenin in rats.[Pubmed:23153055]

Xenobiotica. 2013 May;43(5):479-85.

1. Resibufogenin (1), a major bufadienolide of Chinese medicine Chan Su, had a wide range of pharmacological activities. In present work, the metabolism of 1 in male Sprague-Dawley rats was investigated by identifying the metabolites of Resibufogenin excreted in rat bile. 2. Following an oral dose of 60 mg/kg resibufagenin, nine metabolites were isolated from bile of rats, and their structures were identified as 3-keto- Resibufogenin (2), 3-epi-Resibufogenin (3), 5beta-hydroxy-3-epi-Resibufogenin (4), 1alpha, 5beta-dihydroxy-3-epi-Resibufogenin (5), 3alpha, 5beta, 14alpha, 15beta-tetrahydroxyl-bufa- 20, 22-dienolide (6), 3alpha, 14alpha, 15beta-trihydroxy-bufa-20, 22-dienolide (7), 3-epi- 5beta-hydroxy-bufalin (8), 12alpha, 16beta-dihydroxy-3-epi-Resibufogenin (9), and 5beta, 16beta-dihydroxy-3-epi-Resibufogenin (10), respectively, on the basis of widely spectroscopic methods including 2D-NMR technology. It is first time to describe the metabolites of 1 in vivo, and metabolites 5-7 and 9-10 are novel. 3. On the basis of these identified metabolites, a possible metabolism pathway for 1 in rats has been proposed. This is the first systematic study on the phase I metabolites of Resibufogenin.

Effects of Resibufogenin and Cinobufagin on voltage-gated potassium channels in primary cultures of rat hippocampal neurons.[Pubmed:21798339]

Toxicol In Vitro. 2011 Dec;25(8):1644-53.

Outward delayed rectifier potassium channel and outward transient potassium channel have multiple important roles in maintaining the excitability of hippocampal neurons. The present study investigated the effects of two bufadienolides, Resibufogenin (RBG) and Cinobufagin (CBG), on the outward delayed rectifier potassium current (IK) and outward transient potassium current (IA) in rat hippocampal neurons. RBG and CBG have similar structures and both were isolated from the venom gland of toad skin. RBG inhibited both IK and IA, whereas CBG inhibited IK without noticeable effect on IA. Moreover, at 1 muM concentration both RBG and CBG could alter some channel kinetics and gating properties of IK, such as steady-state activation and inactivation curves, open probability and time constants. These findings suggested that IK is probably a target of bufadienolides, which may explain the mechanisms of bufadienolides' pathological effects on central nervous system.

Characterization of phase I metabolism of resibufogenin and evaluation of the metabolic effects on its antitumor activity and toxicity.[Pubmed:25504504]

Drug Metab Dispos. 2015 Mar;43(3):299-308.

Resibufogenin (RB), one of the major active compounds of the traditional Chinese medicine Chansu, has displayed great potential as a chemotherapeutic agent in oncology. However, it is a digoxin-like compound that also exhibits extremely cardiotoxic effects. The present study aimed to characterize the metabolic behaviors of RB in humans as well as to evaluate the metabolic effects on its bioactivity and toxicity. The phase I metabolic profile in human liver microsomes was characterized systemically, and the major metabolite was identified as marinobufagenin (5beta-hydroxylResibufogenin, 5-HRB) by liquid chromatography-mass spectrometry and nuclear magnetic imaging techniques. Both cytochrome P450 (P450) reaction phenotyping and inhibition assays using P450-selective chemical inhibitors demonstrated that CYP3A4 was mainly involved in RB 5beta-hydroxylation with much higher selectivity than CYP3A5. Kinetic characterization demonstrated that RB 5beta-hydroxylation in both human liver microsomes and human recombinant CYP3A4 obeyed biphasic kinetics and displayed similar apparent kinetic parameters. Furthermore, 5-HRB could significantly induce cell growth inhibition and apoptosis in A549 and H1299 by facilitating apoptosome assembly and caspase activation. Meanwhile, 5-HRB displayed very weak cytotoxicity of human embryonic lung fibroblasts, and in mice there was a greater tolerance to acute toxicity. In summary, CYP3A4 dominantly mediated 5beta-hydroxylation and was found to be a major metabolic pathway of RB in the human liver, whereas its major metabolite (5-HRB) displayed better druglikeness than its parent compound RB. Our findings lay a solid foundation for RB metabolism studies in humans and encourage further research on the bioactive metabolite of RB.

Resibufogenin corrects hypertension in a rat model of human preeclampsia.[Pubmed:16446498]

Exp Biol Med (Maywood). 2006 Feb;231(2):215-20.

The study of the pathogenesis of preeclampsia has been hampered by a relative dearth of animal models. We developed a rat model of preeclampsia in which the excretion of a circulating inhibitor of Na/K ATPase, marinobufagenin (MBG), is elevated. These animals develop hypertension, proteinuria, and intrauterine growth restriction. The administration of a congener of MBG, Resibufogenin (RBG), reduces blood pressure to normal in these animals, as is the case when given to pregnant animals rendered hypertensive by the administration of MBG. Studies of Na/K ATPase inhibition by MBG and RBG reveal that these agents are equally effective as inhibitors of the enzyme.

Resibufogenin prevents the manifestations of preeclampsia in an animal model of the syndrome.[Pubmed:19277924]

Hypertens Pregnancy. 2010 Jan;29(1):1-9.

BACKGROUND AND OBJECTIVES: We have developed a rat model of preeclampsia which is based upon excessive volume expansion and includes hypertension, proteinuria and intrauterine growth restriction. In this model, the urinary excretion of the circulating steroid inhibitor of Na +/ K+ ATPase, marinobufagenin, is increased prior to the development of hypertension and proteinuria. An analogue of marinobufagenin, Resibufogenin, successfully treats the hypertension and proteinuria. METHODS: We administered Resibufogenin early in pregnancy in this model, prior to the development of the syndrome. RESULTS: We found that Resibufogenin not only prevented the advent of hypertension and proteinuria, but also the development of intrauterine growth restriction. DISCUSSION: These results may have relevance to the human condition.

Resibufogenin, a component of huachansu, has been shown to exhibit the anti-proliferative effect against cancer cells, and this may be attributed to the degradation of cyclin D1 caused by the activation of GSK-3β.

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