Phloretin - an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation

JONGE, P.C.; Wieringa, Tjalling; Putten, Jos P. M. van; Michiel, H.; Krans, J. M.; Dam, K. Van

doi:10.1016/0005-2728(83)90177-9

Cited by 39 publications

(18 citation statements)

References 18 publications

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“…K252a was more potent than 2-aminopurine with a maximal inhibitory e ect observed at 30 nM. In a complementary experiment, we also found that phloretin, an uncoupler and inhibitor of mitochondrial oxidative phosphorylation which depletes cellular stores of ATP (De Jonge et al, 1983), completely abolished the serum-dependent expression of MKP-1 in Rat1 cells (data not shown). These results strongly implicate the action of protein kinase(s) in the regulation of MKP-1 expression.…”

Section: Calcium Is Necessary For Induction Of Mkp-1 Gene Expressionmentioning

confidence: 65%

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

et al. 1997

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Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a dual-speci®city protein phosphatase encoded by an immediate-early gene responsive to growth factors and stress. The MKP-1 protein selectively inactivates MAP kinases in vitro by dephosphorylation of the regulatory Thr and Tyr residues. Little is known on the mechanisms that regulate MKP-1 gene expression. Here, we demonstrate that Ca 2+ is both necessary and su cient for the induction of MKP-1 gene expression. Treatment of Rat1 ®broblasts with the Ca 2+ chelating agent BAPTA completely suppressed serum-induced MKP-1 expression in a dose-and timedependent manner. The inhibitory e ect of BAPTA was observed at the level of the protein and the mRNA. Importantly, Ca 2+ chelation blocked the induction of MKP-1 expression in response to all stimuli tested and in di erent cell types. Increasing the intracellular concentration of Ca 2+ with the ionophore A23187 was su cient to induce MKP-1 mRNA and protein expression in rat ®broblasts. We also provide evidence that activation of MAP kinases is not an absolute requirement for induction of the MKP-1 gene. Exposure of rat ®broblasts to A23187 induced MKP-1 expression without activating the JNK and p38 MAP kinase pathways. Also, inhibition of the ERK pathway with the selective MEK inhibitor PD98059 did not interfere with serumstimulated MKP-1 mRNA expression. These results will help de®ne the regulatory mechanisms that govern MKP-1 gene transcription in target cells.

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Section: Calcium Is Necessary For Induction Of Mkp-1 Gene Expressionmentioning

confidence: 65%

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

et al. 1997

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“…Furthermore, the decrease in respiration caused by TAM may reflect other membrane-dependent biological activities of this drug, since TAM, with a pKa ϳ8.5, is a protonated quaternary ammonium cation at the used experimental pH that partitions strongly in biomembranes (Custódio et al, 1991) and decreases its fluidity (Custódio et al, 1993). As reported for a few lipophilic compounds possessing base-and acid-dissociative groups, with characteristics and effects very similar to those of TAM and also known as uncouplers [e.g., AU-1421 (Nagamune et al, 1993), phloretin (Jonge et al, 1983), amiodarone (Fromenty et al, 1990), local anesthetics (Garlid and Nakashima, 1983), and several nongenotoxic carcinogens (Keller et al, 1992)], the ionizable group of TAM could change the membrane surface potential, thereby changing the interactions between the components of the respiratory chain. Additionally, this drug may decrease the diffusional mobility of membrane proteins, according to its rigidifying effects in biomembranes (Custódio et al, 1993), thereby decreasing the rate of electron transfer along the redox system of mitochondria.…”

Section: Fig 5 Effects Of Tam (-) Andmentioning

confidence: 97%

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Cardoso

Custódio

Almeida

et al. 2001

Toxicology and Applied Pharmacology

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Tamoxifen (TAM), the widely prescribed drug in the prevention and therapy of breast cancer, is a well-known modulator of estrogen receptor (ER) that also inhibits the proliferation of different cell types that lack the ER. However, the ER-independent action mechanisms of TAM and its side effects have not been yet clarified. Mitochondria are essential in supporting the energy-dependent regulation of cell functions. Changes in mitochondria result in bioenergetic deficits leading to the loss of vital functions to cell survival. Therefore, this study describes the effects of TAM on mitochondrial bioenergetics, contributing to a better understanding of the biochemical mechanisms underlying the multiple antiproliferative and toxic effects of this drug. TAM at concentrations above 20 nmol/mg protein, preincubated with isolated rat liver mitochondria at 25°C for 3 min, significantly depresses, in a dose-dependent manner, the phosphorylation efficiency of mitochondria as inferred from the decrease in the respiratory control and ADP/O ratios, the perturbations in mitochondrial transmembrane potential (⌬⌿), the fluctuations associated with mitochondrial energization, and the phosphorylative cycle induced by ADP. Furthermore, TAM at up to 40 nmol/mg protein stimulates the rate of state 4 respiration and at higher concentrations it strongly inhibits state 3 and uncouples the mitochondrial respiration. The stimulation of state 4 respiration parallels the decrease of ⌬⌿ as a consequence of proton permeability. The TAM-stimulatory action of ATPase is also observed in intact mitochondria, suggesting that TAM promotes extensive permeability to protons due to destructive effects in the structural integrity of the mitochondrial inner membrane. These multiple effects of TAM on mitochondrial bioenergetic functions, causing changes in the respiration, phosphorylation efficiency, and membrane structure, may explain the cell death induced by this drug in different cell types, its anticancer activity in ER-negative cells, and its side effects. © 2001 Academic Press Key Words: tamoxifen; anticancer drug; mitochondria; respiration rate; mitochondrial transmembrane potential; mitochondrial proton leak; membrane disruption.Tamoxifen (TAM) is the most used nonsteroidal antiestrogen drug for chemotherapy and chemoprevention of breast cancer (Neven and Vernaeve, 2000;Radmacher and Simon, 2000). The antiproliferative effects of TAM in estrogen-dependent breast cancer cells are mediated by high-affinity binding to the estrogen receptor (ER) (Coezy et al., 1982). However, TAM inhibits also the growth of ER-negative breast cancer cells and other cell types that lack ER (Couldwell et al., 1993;Croxtall et al., 1994;Charlier et al., 1995). Actually, TAM has been reported to have several physiological effects that are ER independent, including sensitization of resistant tumor cells to many chemotherapeutic agents (Altan et al., 1999) and several pleiotropic effects both in vivo and in vitro and references therein). Moreover, it has been reported that...

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“…Phloretin blocks GLUT transport and facilitates diffusion of urea and glycerol, as well as inhibits membrane transport of chloride, bicarbonate, and lithium in mammalian erythrocytes, but does not affect SGLTs [77,78]. Phloretin can uncouple mitochondrial oxidative phosphorylation [79]. Using the response of an estrogensensitive promoter sequence from the vitellogenin A2 gene of Xenopus laevis, which controls the expression of a bacterial CAT gene introduced into HeLa cells, phloretin has been shown to possess modest estrogenic activity [80].…”

Section: Phlorizin Pharmacologymentioning

confidence: 99%

Phlorizin: a review

Ehrenkranz

Lewis

Kahn

et al. 2004

Diabetes Metabolism Res

848

633

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The dihydrochalcone phlorizin is a natural product and dietary constituent found in a number of fruit trees. It has been used as a pharmaceutical and tool for physiology research for over 150 years. Phlorizin's principal pharmacological action is to produce renal glycosuria and block intestinal glucose absorption through inhibition of the sodium-glucose symporters located in the proximal renal tubule and mucosa of the small intestine. This review covers the role phlorizin has played in the history of diabetes mellitus and its use as an agent to understand fundamental concepts in renal physiology as well as summarizes the physiology of cellular glucose transport and the pathophysiology of renal glycosuria. It reviews the biology and pathobiology of glucose transporters and discusses the medical botany of phlorizin and the potential effects of plant flavonoids, such as phlorizin, on human metabolism. Lastly, it describes the clinical pharmacology and toxicology of phlorizin, including investigational uses of phlorizin and phlorizin analogs in the treatment of diabetes, obesity, and stress hyperglycemia.

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Phloretin - an uncoupler and an inhibitor of mitochondrial oxidative phosphorylation

Cited by 39 publications

References 18 publications

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression

Mechanisms of the Deleterious Effects of Tamoxifen on Mitochondrial Respiration Rate and Phosphorylation Efficiency

Phlorizin: a review

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