Singulair Intestinal Epithelial Cells, Arnold Diaz, Plasma Proteins, Experimental Pathology, Pathology Department

Leukotriene receptor cysLT1 in intestinal epithelial cells and variation in montelukast blood levels between individuals.

We know many things about this topic:

1. Montelukast enters the blood stream through the intestines
2. the cysLT1 (receptor that Singulair blocks) exists in intestinal epithelial cells
3. montelukast will bind with high affinity to the ideal gene type cysLT1 receptor
4. after montelukast enters into the blood stream is it 99% bound to plasma proteins (that point is hypothesized to be the reason that montelukast does not inhibit CYP2C8 in vivo but it does in vitro if it is true that in vivo it does not inhibit CYP2C8)
5. there is variation between individuals on how much montelukast makes it into the blood stream

Well, did anybody out there in science land think of trying to find out how much montelukast binds to the cysLT1 receptors in intestinal epithelial cells? They got all interested in transport proteins but where are the studies about the cysLT1 receptors in intestinal epithelial. And, what is the effect of montelukast if it binds to intestinal cysLT1receptors?

Now, concernedcitizen believes that if montelukast binds to intestinal epithelial cysLT1receptors that could be a BIG problem because those receptors have a different function than in respiratory tissue. In the one place, we gotta' breathe. In the other place, we gotta' digest food properly.

We have all of these children who have stomach pain. Does anybody want to find out why?

This drug belongs in the science HALL OF SHAME. Somebody please call Arnold Diaz. I am quite discussed today.

Oncogene. 2006 Oct 26;25(50):6660-5. Epub 2006 May 22. Links
Endogenous production of leukotriene D4 mediates autocrine survival and proliferation via CysLT1 receptor signalling in intestinal epithelial cells.Paruchuri S, Mezhybovska M, Juhas M, Sjölander A.
Cell and Experimental Pathology, Department of Laboratory Medicine, Lund University, Malmö University Hospital, Malmö, Sweden.

The cysteinyl leukotriene1 (CysLT1) receptor (CysLT1R) enhances survival and proliferation of intestinal cells via distinct pathways. Here, we have demonstrated that there is significant endogenous production of CysLTs from both non-tumour- and tumour-derived intestinal epithelial cells. Treatment of two non-tumour cell lines, Int 407 and IEC-6, with CysLT1R antagonists led to shrinkage and detachment of cells, confirmed as apoptotic cell death, and a dose-dependent reduction in proliferation. However, in the tumour intestinal cell lines Caco-2, SW480, HCT-116 and HT-29, treatment with CysLT1R antagonists significantly reduced proliferation, but had no effect on apoptosis. A unique characteristic of intestinal cancer cells is the presence of nuclear CysLT1Rs, which are inaccessible to receptor antagonists. In these cells, inhibition of the endogenous production of CysLTs indirectly, by 5-lipoxygenase inhibition, impaired CysLT1R signalling throughout the cell, and resulted in apoptosis of the tumour cells. These data reveal the existence of constitutive CysLT1R signalling that mediates both survival and proliferation in intestinal cells. Importantly, we propose that tumour-derived intestinal cells are resistant to CysLT1R antagonist-induced apoptosis, a phenomena that could be explained by nuclear CysLT1R signalling.

PMID: 16715140 [PubMed - indexed for MEDLINE]

CLINICAL TRIAL - transport proteins and montelukast

http://clinicaltrials.gov/ct2/show/record/NCT00513760