Teratogen update: Azathioprine and 6‐mercaptopurine

Polifka, Janine E.; Friedman, Jan M.

doi:10.1002/tera.10043

Cited by 209 publications

(138 citation statements)

References 208 publications

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“…25 The dose at which azathioprine is applied chronically in transplantation protocols and inflammatory bowel disease does not invoke systemic cytostatic effects and is even compatible with normal pregnancy. 26 Over the years, cyclosporin A has replaced azathioprine as a drug in these pathologies; however, patients treated with cyclosporin A are at relatively high risk for cardiovascular disease. 27,28 Consequently, the prescription of azathioprine currently is undergoing a revival in clinical practice, with beneficial effects on lipid profiles, extent of plasma low-density lipoprotein oxidation, and fibrinolytic parameters.…”

Section: Discussionmentioning

confidence: 99%

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Pires¹,

Pols²,

Vries³

et al. 2007

Circulation

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Background-Restenosis is a common complication after percutaneous coronary interventions and is characterized by excessive proliferation of vascular smooth muscle cells (SMCs). We have shown that the nuclear receptor Nur77 protects against SMC-rich lesion formation, and it has been demonstrated that 6-mercaptopurine (6-MP) enhances Nur77 activity. We hypothesized that 6-MP inhibits neointima formation through activation of Nur77. Methods and Results-It is demonstrated that 6-MP increases Nur77 activity in cultured SMCs, which results in reduced [ 3 H]thymidine incorporation, whereas Nur77 small interfering RNA knockdown partially restores DNA synthesis. Furthermore, we studied the effect of 6-MP in a murine model of cuff-induced neointima formation. Nur77 mRNA is upregulated in cuffed arteries, with optimal expression after 6 hours and elevated expression up to 7 days after vascular injury. Local perivascular delivery of 6-MP with a drug-eluting cuff significantly inhibits neointima formation in wild-type mice. Locally applied 6-MP does not affect inflammatory responses or apoptosis but inhibits expression of proliferating cell nuclear antigen and enhances protein levels of the cell-cycle inhibitor p27 Kip1 in the vessel wall. An even stronger inhibition of neointima formation in response to local 6-MP delivery was observed in transgenic mice that overexpressed Nur77. In contrast, 6-MP does not alter lesion formation in transgenic mice that overexpress a dominant-negative variant of Nur77 in arterial SMCs, which provides evidence for the involvement of Nur77-like factors. Conclusions-Enhancement of the activity of Nur77 by 6-MP protects against excessive SMC proliferation and SMC-rich neointima formation. We propose that activation of the nuclear receptor Nur77 is a rational approach to treating in-stent restenosis. (Circulation. 2007;115:493-500.)

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Section: Discussionmentioning

confidence: 99%

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Pires¹,

Pols²,

Vries³

et al. 2007

Circulation

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“…Mrp4 was functionally defined as a nucleotide monophosphate efflux transporter (6) and later found to export cyclic nucleotides in an energy-dependent fashion (7,8) because of latter role of Mrp4 and the effect of Mrp4 substrates (e.g. thiopurines (7) and methotrexate (9)) and inhibitors (nonsteroidal anti-inflammatory drugs (10)) on androgen response (11) and fertility (12,13), we hypothesized that Mrp4 regulates testosterone production.…”

mentioning

confidence: 99%

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Morgan

Cheepala

Wang

et al. 2012

Journal of Biological Chemistry

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Background:The role of the ABC transporter, Mrp4, in regulating Leydig cell testosterone synthesis is unknown. Results: In a murine genetic model the absence of Mrp4 impairs testosterone production by disrupting cAMP signaling. Conclusion: Mrp4 absence disrupts Leydig cell cAMP homeostasis by impairing luteinizing hormone-activated testosterone production. Significance: These findings reveal a mechanism for unexplained side effects of altered androgen production by therapeutics disrupting Mrp4 function.

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“…In these studies, congenital anomaly rates were between 0.0%-11.8%, and congenital anomalies that showed a recurrent pattern were not established (24 Table-4 shows effect of 5-ASA, AZA and CS on pregnancy outcomes.…”

Section: ) Thiopurinesmentioning

confidence: 97%

Safety of drugs used in cases with ulcerative colitis during pregnancy and lactation

Kalkan¹,

Dağlı²

2012

Turk J Gastroenterol

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Teratogen update: Azathioprine and 6‐mercaptopurine

Cited by 209 publications

References 208 publications

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Activation of Nuclear Receptor Nur77 by 6-Mercaptopurine Protects Against Neointima Formation

Deregulated Hepatic Metabolism Exacerbates Impaired Testosterone Production in Mrp4-deficient Mice

Safety of drugs used in cases with ulcerative colitis during pregnancy and lactation

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