Basic-alimentary tractPrevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor☆
Section snippets
Cell lines, animals, human tissues, and compounds
T84 and Caco-2 cells were obtained from the UCSF cell culture facility. T84 cells were cultured in a 1:1 mixture of DMEM and Hams F12 supplemented with 5% fetal calf serum, 100 U/mL penicillin, and 100 μg/mL streptomycin and plated on Snapwell inserts (Corning Costar) for growth in a humidified (5% O2/95% CO2) atmosphere at 37°C. Cells were used at 10–14 days after plating. Caco-2 cells were cultured in DMEM containing 10% fetal calf serum, 1% nonessential amino acids, 100 U/mL penicillin, and
Results
We reported previously that a single intraperitoneal injection of CFTRinh-172 in mice inhibited cholera toxin-stimulated fluid secretion in a closed intestinal loop model.14 These initial observations were extended by measurement of the dose-response relationship and the apparent half-time for persistence of the CFTRinh-172 inhibitory effect.
First, the kinetics of intestinal loop fluid absorption and secretion were determined to characterize the mouse model. To study absorption, loop fluid
Discussion
The purpose of this study was to evaluate the potential antidiarrheal properties of a small-molecule CFTR inhibitor identified recently by high-throughput screening of a collection of diverse, drug-like compounds and optimization of thiazolidinone analogs.14 The best CFTR blocker, CFTRinh-172, inhibited CFTR Cl− conductance reversibly at submicromolar concentrations without inhibiting/activating a series of other channels and transporters, including the ABC (ATP binding cassette) transporters
References (34)
- et al.
Global progress in the control of diarrheal diseases
Pediatr Infect Dis
(1990) - et al.
The magnitude of the global problem of diarrhoeal diseasea ten-year update
Bull WHO
(1992) - et al.
Estimates of morbidity and mortality rates for diarrheal diseases in American children
J Pediatr
(1991) - et al.
Diarrheal deaths in the United States, 1979 through 1987. A special problem for the elderly
JAMA
(1991) - et al.
Oral rehydration solution in the year 2000pathophysiology, efficacy and effectiveness
Baillieres Clin Gastroenterol
(1997) - et al.
The role of antibiotics in the treatment of infectious diarrhea
Gastroenterol Clin North Am
(2001) - et al.
Enteric bacterial toxinsmechanisms of action and linkage to intestinal secretion
Microbiol Rev
(1996) Escherichia coli cytotoxins and enterotoxins
Can J Microbiol
(1992)- et al.
Chloride secretion by the intestinal epitheliummolecular basis and regulatory aspects
Annu Rev Physiol
(2000) - et al.
Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model
Science
(1994)
Activation of intestinal CFTR Cl− channel by heat-stable enterotoxin and guanylin via cAMP-dependent protein kinase
EMBO J
Electrolyte transport in the mammalian colonmechanisms and implications for disease
Physiol Rev
Inhibition of enterotoxin-induced porcine colonic secretion by diarylsulfonylureas in vitro
Am J Physiol
Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera-toxin induced intestinal fluid secretion
J Clin Invest
Antidiarrheal properties and pharmacology of a small molecule CFTR inhibitor
Ped Pulmonol
Acute undifferentiated human diarrhea in the tropics. I. Alterations in intestinal microflora
J Clin Invest
Identification in traditional herbal medications and confirmation by synthesis of factors that inhibit cholera toxin-induced fluid accumulation
Proc Natl Acad Sci U S A
Cited by (0)
- ☆
Supported by a drug discovery grant from the Cystic Fibrosis Foundation; grants HL60288, HL73856, EB00415, EY13574, and DK35124 from the National Institutes of Health; a Cystic Fibrosis Foundation fellowship (to J.R.T.); and student fellowships from the American Heart Association, Western States Affiliate (to T.B. and E.H.).