Inhibition of Gastric H<sup>+</sup>,K<sup>+</sup>-ATPase by Flavonoids: A Structure-Activity Study

Murakami, Shigeru; Murata, Makoto; Tomisawa, Kazuyuki

doi:10.3109/14756369909036551

Cited by 49 publications

(37 citation statements)

References 25 publications

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“…In addition to the importance of hydroxyl group at position 3, since neither flavones nor chalcones had any preventive effect, the oxidation of the 2, 3-bond was critical since silybin was inefficient. These requirements are similar to those observed for quercetin binding to the Hck tyrosine kinase as demonstrated by cocrystallization [82], and for other ATPases by inhibition kinetics [88]. In contrast, they differ from those concerning the cyclindependent CDK2, the crystal structure of which was determined with bound chrysin derivatives [80].…”

Section: Flavonoid Molecular Interactions With P-glycoprotein and Relmentioning

confidence: 73%

“…Recognition of the ATP-binding site in various ATPases requires the presence of three hydroxyl groups at A-ring positions 5 and 7, and C-ring position 3, which favors some flavonols [88]. On the contrary, protein kinases exhibit different requirements: an isoflavone structure for tyrosin kinases [81], or flavones substituted at A-ring position 8 for CDK2 [80].…”

Section: Different Flavonoid Structure-activity Relationships For Dismentioning

confidence: 99%

“…The latter effects are mediated through two types of action: antiestrogen activity [78] due to mimicking of hormones (flavonoids are therefore often considered as 'phytoestrogens'), and inhibition of a series of protein kinases and ATP(adenosine 5¢-triphosphate)ases due to mimicking of the ATP-adenine base. Among the latter are serine/threonine kinases [79,80], tyrosine kinases [81,82], topoisomerase II [83], myosin [84] as well as various membrane ATPases: mitochondrial H + -ATPase [85], Na + /K + -ATPase [86], Ca 2+ -ATPase [87] or H + /K + -ATPase [88].…”

Section: Flavonoids: a Large Family Of Natural Compounds With A Numbementioning

confidence: 99%

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Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Pietro

Conseil

Pérez‐Victoria

et al. 2002

CMLS, Cell. Mol. Life Sci.

228

168

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Cancer cell resistance to chemotherapy is often mediated by overexpression of P-glycoprotein, a plasma membrane ABC (ATP-binding cassette) transporter which extrudes cytotoxic drugs at the expense of ATP hydrolysis. P-glycoprotein (ABCB1, according to the human gene nomenclature committee) consists of two homologous halves each containing a transmembrane domain (TMD) involved in drug binding and efflux, and a cytosolic nucleotide-binding domain (NBD) involved in ATP binding and hydrolysis, with an overall (TMD-NBD)2 domain topology. Homologous ABC multidrug transporters, from the same ABCB family, are found in many species such as Plasmodiumfalciparum and Leishmania spp. protozoa, where they induce resistance to antiparasitic drugs. In yeasts, some ABC transporters involved in resistance to fungicides, such as Saccharomyces cerevisiae Pdr5p and Snq2p, display a different (NBD-TMD)2 domain topology and are classified in another family, ABCG. Much effort has been spent to modulate multidrug resistance in the different species by using specific inhibitors, but generally with little success due to additional cellular targets and/or extrusion of the potential inhibitors. This review shows that due to similarities in function and maybe in three-dimensional organization of the different transporters, common potential modulators have been found. An in vitro 'rational screening' was performed among the large flavonoid family using a four-step procedure: (i) direct binding to purified recombinant cytosolic NBD and/or full-length transporter, (ii) inhibition of ATP hydrolysis and energy-dependent drug interaction with transporter-enriched membranes, (iii) inhibition of cell transporter activity monitored by flow cytometry and (iv) chemosensitization of cell growth. The results indicate that prenylated flavonoids bind with high affinity, and strongly inhibit drug interaction and nucleotide hydrolysis. As such, they constitute promising potential modulators of multidrug resistance.

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Section: Flavonoid Molecular Interactions With P-glycoprotein and Relmentioning

confidence: 73%

Section: Different Flavonoid Structure-activity Relationships For Dismentioning

confidence: 99%

Section: Flavonoids: a Large Family Of Natural Compounds With A Numbementioning

confidence: 99%

See 1 more Smart Citation

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Pietro

Conseil

Pérez‐Victoria

et al. 2002

CMLS, Cell. Mol. Life Sci.

228

168

View full text Add to dashboard Cite

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“…Preliminary structure-activity relationships with the Leishmania MDR line have allowed the rational design of a flavonoid derivative meeting all of the requirements reported to increase interaction with the cytosolic NBDs of LtrMDR1, especially (i) ring B connected to position 2 of ring C (7, 34), (ii) oxidized 2,3 bond of ring C (34, 37) (interestingly, reduction of this 2,3 double bond of similar flavonoids also resulted in a decreased competitive inhibition of H ϩ ,K ϩ -ATPase with respect to ATP [28]), (iii) a monolignol unit adjacent to ring B (37), (iv) hydroxyl groups at position 3 of ring C and position 5 of ring A (34) (this hydroxyl group also favored ATP mimetism [12,43] and competitive inhibition of Hϩ,Kϩ-ATPase with respect to ATP [28]), and (v) a hydrophobic substitution at position 8 of ring A with 1,1-dimethylallyl, as deduced when comparing different prenyl substitutions (1,1-dimethylallyl Ͼ prenylation Ͼ geranylation) at different positions of ring A (position 8 Ͼ position 6) (37). The resulting compound, 8-(1,1-DMA)-DHS, was hemisynthesized starting from the therapeutic agent silybin (M.M., D.B., et al, unpublished data), which explains the additional OH at position 7 of ring A, known not to affect the interaction with the NBDs (7,34), and its structure is show in Fig.…”

Section: Resultsmentioning

confidence: 99%

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

Pérez‐Victoria

Cortés-Selva

Parodi-Talice

et al. 2006

Antimicrob Agents Chemother

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Miltefosine (hexadecylphosphocholine) is the first orally active drug approved for the treatment of leishmaniasis. We have previously shown the involvement of LtrMDR1, a P-glycoprotein-like transporter belonging to the ATP-binding cassette superfamily, in miltefosine resistance in Leishmania. Here we show that overexpression of LtrMDR1 increases miltefosine efflux, leading to a decrease in drug accumulation in the parasites. Although LtrMDR1 modulation might be an efficient way to overcome this resistance, a main drawback associated with the use of P-glycoprotein inhibitors is related to their intrinsic toxicity. In order to diminish possible side effects, we have combined suboptimal doses of modulators targeting both the cytosolic and transmembrane domains of LtrMDR1. Preliminary structure-activity relationships have allowed us to design a new and potent flavonoid derivative with high affinity for the cytosolic nucleotide-binding domains. As modulators directed to the transmembrane domains, we have selected one of the most potent dihydro-␤-agarofuran sesquiterpenes described, and we have also studied the effects of two of the most promising, latest-developed modulators of human P-glycoprotein, zosuquidar (LY335979) and elacridar (GF120918). The results show that this combinatorial strategy efficiently overcomes P-glycoprotein-mediated parasite miltefosine resistance by increasing intracellular miltefosine accumulation without any side effect in the parental, sensitive, Leishmania line and in different mammalian cell lines.

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“…Flavonoids such as quercetin have been recently reported to inhibit gastric H þ K þ ATPase activity dose-dependently (Murakami et al, 1999). CVE reduced the level of…”

Section: Discussionmentioning

confidence: 99%

Protective effect of standardized extract ofCleome viscosaagainst experimentally induced gastric lesions in the rat

Gupta

Rao

Sharma

2013

Pharmaceutical Biology

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Context: Cleome viscosa Linn. (Capparidaceae) is used traditionally in the Indian system of medicine as a carminative, anthelmintic, and diuretic, and used for healing wounds, ulcers and diarrhea. Objective: A 70% ethanol (EtOH) extract of the aerial parts of Cleome viscosa extract (CVE) was investigated for gastroprotective activity in different gastric ulcer models in order to validate ethnobotanical claims regarding the plant use in ulcers. Materials and methods: CVE (100, 200 and 400 mg/kg body weight) was administered orally, twice daily for 5 d, for prevention from EtOH, pylorus ligation (PL) and cold restraint stress (CRS)-induced ulcers in rats. Estimation of H þ K þ ATPase activity and gastric wall mucous were performed in EtOH-induced ulcer, antioxidant enzyme activities in supernatant mitochondrial fraction of CRS-induced ulcer, and gastric secretion parameters were estimated in PL-induced ulcer model Results: CVE showed significant (p50.01) dose-dependent inhibition of lesion index in EtOH 15.93-42.30%, PL 26.34-59.28% and CRS 22.58-54.03%, respectively. CVE prevents the oxidative damage of gastric mucosa by blocking lipid peroxidation and by a significant (p50.001) decrease in superoxide dismutase, and an increase in catalase activity. A significant (p50.01) decrease occurred in the level of H þ K þ ATPase, volume of gastric juice and total acidity. Simultaneously, the level of gastric wall mucus and pH were increased significantly (p50.05). High performance thin layer chromatography analysis showed the presence of quercetin and gallic acid (0.3% and 0.25% w/w, respectively) in CVE. Conclusions: Results of our study showed that C. viscosa possesses significant gastroprotective activity, probably due to free radical scavenging activity, and validates the folklore claim.

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Inhibition of Gastric H⁺,K⁺-ATPase by Flavonoids: A Structure-Activity Study

Cited by 49 publications

References 25 publications

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

Protective effect of standardized extract ofCleome viscosaagainst experimentally induced gastric lesions in the rat

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Inhibition of Gastric H+,K+-ATPase by Flavonoids: A Structure-Activity Study

Cited by 49 publications

References 25 publications

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

Protective effect of standardized extract ofCleome viscosaagainst experimentally induced gastric lesions in the rat

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Inhibition of Gastric H⁺,K⁺-ATPase by Flavonoids: A Structure-Activity Study