Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Mitin, Tim; Moltke, Lisa L. von; Court, Michael H.; Greenblatt, David J.

doi:10.1124/dmd.32.8.779

Cited by 47 publications

(32 citation statements)

References 28 publications

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“…To address this possibility, first we have studied the effect of tetrac on expression of Pglycoprotein, SOD, and GST-p and found that expression of none of these genes was significantly altered (Fig 3). Others have shown that agonist thyroid hormone can increase expression of P-gp [26,27]. Tetrac, at the concentrations used, exerts its thyroid hormone antagonist activity primarily at the integrin receptor.…”

Section: Discussionmentioning

confidence: 97%

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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Section: Discussionmentioning

confidence: 97%

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

et al. 2008

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“…5). Mitin et al 19) reported that P-gp, but not CYP3A2, is induced by LTX (100 mM) in human colon carcinoma cells (LS180 and Caco-2) in vitro, and the induction is mediated by thyroid hormone receptor (TR) rather than PXR. Our results are consistent with this.…”

Section: Discussionmentioning

confidence: 99%

Long-term Levothyroxine Treatment Decreases the Oral Bioavailability of Cyclosporin A by Inducing P-glycoprotein in Small Intestine

Jin

Shimada

Shintani

et al. 2005

Drug Metabolism and Pharmacokinetics

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Summary:We have noticed that the trough level of blood concentration of cyclosporin A (CyA) tends to be lower in patients receiving long-term oral levothyroxine (LTX) than in patients not receiving LTX. We conˆrmed this clinical observation in experiments using Wistar rats orally given LTX (8 mg W kg) or saline (control) for 3 weeks, followed by CyA (10 mg W kg). The LTX treatment had little eŠect on the blood concentrations of CyA after i.v. administration, whereas they were decreased signiˆcantly after p.o. administration. After p.o. administration, the value of the area under the blood concentration-time curve from 0 to 24 hr and the bioavailability of CyA in the LTX group were decreased to only about onefth and a quarter of those in the control group, respectively. After treatment with LTX, the expression levels of mdr1a, mdr1b and CYP3A2 mRNAs in the duodenum were markedly increased to about twice the control, but in jejunum, ileum and liver the expression levels were little changed. Theseˆndings suggest that the absorption of CyA, which occurs mainly from the upper intestine, is reduced as a result of eOEux transport via P-glycoprotein induced by LTX. In conclusion, careful monitoring of CyA levels is required in the event of LTX administration to patients receiving immunotherapy with CyA.

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“…In various cells, this antibiotic induces P-glycoprotein, thus notably altering the physiology of these cells (Greiner et al 1999;Asghar et al 2002;Collett et al 2004;Granzotto et al 2004;Mitin et al 2004).…”

Section: Resultsmentioning

confidence: 98%

Mycobacterium avium–intracellulare contamination of mammalian cell cultures

Lelong-Rebel

Piémont

Fabre

et al. 2008

In Vitro Cell.Dev.Biol.-Animal

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Mycobacterium avium contamination has been described as a putative contaminant of nonphagocytic mammalian cells. Screening of numerous cultured nonphagocytic mammalian cell lines revealed the presence of intracellular bacteria that were identified as M. avium-intracellulare. An extensive and critical analysis of the origin of infection, of cure protocols, and of biological manifestations in M. avium-infected cells is presented. As no tremendous visible alteration of turbidity or pH of cell culture media, and no morphological change occurred in most M. avium-infected cell cultures, detection of an infection by these bacteria is rather difficult. Recommendations are given for treatment of irreplaceable cultures and prevention of mycobacterial contamination in a tissue culture facility.

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Levothyroxine Up-Regulates P-Glycoprotein Independent of the Pregnane X Receptor

Cited by 47 publications

References 28 publications

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

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

Long-term Levothyroxine Treatment Decreases the Oral Bioavailability of Cyclosporin A by Inducing P-glycoprotein in Small Intestine

Mycobacterium avium–intracellulare contamination of mammalian cell cultures

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