Thyroid hormone export from cells: contribution of P-glycoprotein

Mitchell, Angela M.; Tom, Moshe; Mortimer, Robin H.

doi:10.1677/joe.1.06096

Cited by 43 publications

(28 citation statements)

References 27 publications

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“…TIM was previously characterized to be an inhibitor of several mammalian efflux pumps (25,26,31,32) and enhanced the potency of antibiotics against Gram-positive bacteria in broth cultures (15). The importance of evaluating efflux inhibitors in multiple relevant disease models is represented by the work in this study, where different efflux inhibitor-antibiotic combinations had different effects on mycobacterial growth in MIC assays, infected macrophage assays, and mouse infections.…”

Section: Discussionmentioning

confidence: 94%

The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

Grossman

Shoen

Jones

et al. 2015

Antimicrob Agents Chemother

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bPrevious studies indicated that inhibition of efflux pumps augments tuberculosis therapy. In this study, we used timcodar (formerly VX-853) to determine if this efflux pump inhibitor could increase the potency of antituberculosis (anti-TB) drugs against Mycobacterium tuberculosis in in vitro and in vivo combination studies. When used alone, timcodar weakly inhibited M. tuberculosis growth in broth culture (MIC, 19 g/ml); however, it demonstrated synergism in drug combination studies with rifampin, bedaquiline, and clofazimine but not with other anti-TB agents. When M. tuberculosis was cultured in host macrophage cells, timcodar had about a 10-fold increase (50% inhibitory concentration, 1.9 g/ml) in the growth inhibition of M. tuberculosis and demonstrated synergy with rifampin, moxifloxacin, and bedaquiline. In a mouse model of tuberculosis lung infection, timcodar potentiated the efficacies of rifampin and isoniazid, conferring 1.0 and 0.4 log 10 reductions in bacterial burden in lung, respectively, compared to the efficacy of each drug alone. Furthermore, timcodar reduced the likelihood of a relapse infection when evaluated in a mouse model of long-term, chronic infection with treatment with a combination of rifampin, isoniazid, and timcodar. Although timcodar had no effect on the pharmacokinetics of rifampin in plasma and lung, it did increase the plasma exposure of bedaquiline. These data suggest that the antimycobacterial drug-potentiating activity of timcodar is complex and drug dependent and involves both bacterial and host-targeted mechanisms. Further study of the improvement of the potency of antimycobacterial drugs and drug candidates when used in combination with timcodar is warranted.

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Section: Discussionmentioning

confidence: 94%

The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

Grossman

Shoen

Jones

et al. 2015

Antimicrob Agents Chemother

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“…3c) and suggested that tetrac may act as an inhibitor of P-gp activity. In light of the previous observation that thyroid hormones are able to bind to avb3 integrin [8] and to P-gp [28], the finding that tetrac inhibits their binding to integrins raises the possibility that tetrac may also interfere with their binding to Pgp. Using the same logic, tetrac may also compete with drugs for the binding to P-gp and thus, disrupt the efficacy of this transporter.…”

Section: Discussionmentioning

confidence: 98%

Novel function of the thyroid hormone analog tetraiodothyroacetic acid: a cancer chemosensitizing and anti-cancer agent

et al. 2008

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Previous studies from our laboratory have demonstrated that thyroid hormones play a key role in cancer progression. In addition, a deaminated form, tetraiodothyroacetic acid (tetrac), that antagonizes the proliferative action of these hormones was found to possess anti-cancer functions through its ability to inhibit cellular proliferation and angiogenesis. The present study was undertaken to investigate whether tetrac could also suppress the development of drug resistance, known as a causative factor of disease relapse. Tetrac was shown to enhance cellular response in vitro to doxorubicin, etoposide, cisplatin, and trichostatin A in resistant tumor cell lines derived from neuroblastoma, osteosarcoma, and breast cancer. The mechanism of action of tetrac did not involve expression of classical drug resistance genes. However, radiolabeled doxorubicin uptake in cells was enhanced by tetrac, suggesting that one or more export mechanisms for chemotherapeutic agents are inhibited. Tetrac was also found to enhance cellular susceptibility to senescence and apoptosis, suggesting that the agent may target multiple drug resistance mechanisms. Tetrac has previously been shown to inhibit tumor cell proliferation in vitro. In vivo studies reported here revealed that tetrac in a pulsed-dose regimen was effective in suppressing the growth of a doxorubicin-resistant human breast tumor in the nude mouse. In this paradigm, doxorubicin-sensitivity was not restored, indicating that (1) the in vitro restoration of drug sensitivity by tetrac may not correlate with in vivo resistance phenomena and (2) tetrac is an effective chemotherapeutic agent in doxorubicin-resistant cells.

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“…Subsequent biotransformation reactions are catalyzed by UGTs and SULTs. Conjugated and unconjugated molecules are then excreted into bile via transporters localized on the canalicular membranes such as multidrug resistance-associated proteins (44,67). It will therefore be of interest to determine the extent to which canalicular transport of THs and other hormones is regulated by fasting and cAMP.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor α, and the Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator-1α

Ding

Lichti

Kim

et al. 2006

Journal of Biological Chemistry

134

118

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Animal studies reveal that fasting and caloric restriction produce increased activity of specific metabolic pathways involved in resistance to weight loss in liver. Evidence suggests that this phenomenon may in part occur through the action of the constitutive androstane receptor (CAR, NR1I3). Currently, the precise molecular mechanisms that activate CAR during fasting are unknown. We show that fasting coordinately induces expression of genes encoding peroxisome proliferator-activated receptor ␥ coactivator-1␣ (PGC-1␣), CAR, cytochrome P-450 2b10 (Cyp2b10), UDP-glucuronosyltransferase 1a1 (Ugt1a1), sulfotransferase 2a1 (Sult2a1), and organic anion-transporting polypeptide 2 (Oatp2) in liver in mice. Treatments that elevate intracellular cAMP levels also produce increased expression of these genes in cultured hepatocytes. Our data show that PGC-1␣ interaction with hepatocyte nuclear factor 4␣ (HNF4␣, NR2A1) directly regulates CAR gene expression through a novel and evolutionarily conserved HNF4-response element (HNF4-RE) located in its proximal promoter. Expression of PGC-1␣ in cells increases CAR expression and ligand-independent CAR activity. Genetic studies reveal that hepatic expression of HNF4␣ is required to produce fasting-inducible CAR expression and activity. Taken together, our data show that fasting produces increased expression of genes encoding key metabolic enzymes and an uptake transporter protein through a network of interactions involving cAMP, PGC-1␣, HNF4␣, CAR, and CAR target genes in liver. Given the recent finding that mice lacking CAR exhibit a profound decrease in resistance to weight loss during extended periods of caloric restriction, our findings have important implications in the development of drugs for the treatment of obesity and related diseases.Energy homeostasis must be tightly regulated. In humans, long term energy imbalance can lead to various diseases (1-3). For example, obesity develops when energy intake exceeds energy expenditure over time. On the other hand, cachexia results when energy expenditure exceeds energy intake over a period of time. During caloric restriction or fasting, mammals exhibit a significant decrease in basal metabolic rate in an effort to maintain energy homeostasis and prolong life. It has been shown that starvation can decrease the basal metabolic rate as much as 40% (4). Although the decrease in basal metabolic rate represents a defense mechanism for mammals to survive during times of food shortage, it also creates a barrier to weight loss in obese individuals during caloric restriction.Serum thyroid hormones (THs) 2 and other hormones, including cortisol and leptin, are important molecular signals that modulate weight loss and energy homeostasis in mammals. THs are synthesized by the thyroid gland and are metabolized in peripheral tissues. The major forms of THs are thyroxine (T4) and triidothyronine (T3), with T3 being the biologically active form. T3 performs its function primarily through its agonist activity against the thyroid hormone receptor ...

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Thyroid hormone export from cells: contribution of P-glycoprotein

Cited by 43 publications

References 27 publications

The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

The Efflux Pump Inhibitor Timcodar Improves the Potency of Antimycobacterial Agents

Novel function of the thyroid hormone analog tetraiodothyroacetic acid: a cancer chemosensitizing and anti-cancer agent

Regulation of Constitutive Androstane Receptor and Its Target Genes by Fasting, cAMP, Hepatocyte Nuclear Factor α, and the Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator-1α

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