ToxSci Advance Access published online on August 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh254
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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1 Safety Assessment US, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19850 USA
* To whom correspondence should be addressed. E-mail: Paul.Ciaccio{at}AstraZeneca.com.
It is anticipated that
Accepted August 11, 2004
Systems Toxicology
Modulation of Notch Processing by
-Secretase Inhibitors Causes Intestinal Goblet Cell Metaplasia and Induction of Genes Known to Specify Gut Secretory Lineage Differentiation
2 Safety Assessment UK, AstraZeneca Pharmaceuticals, 23F38 Mereside, Alderley Park, Macclesfield, Cheshire, England, SK10 4TG, UK
3 DMPK, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19850 USA
4 Neuroscience, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19850 USA
5 Chemistry, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19850 USA
6 Target Biology, AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE, 19850 USA
Abstract 
-secretase inhibitors (-Sec-I) which modulate Notch processing will alter differentiation in tissues whose architecture is governed by Notch signaling. To explore this hypothesis, Han Wistar rats were dosed for up to 5 days with 10-100 µmol/kg bid -Sec-I from 3 chemical series that inhibit Notch processing in vitro at various potencies (Notch IC50). These included an arylsulfonamide (AS) (142 nM), a dibenzazepine (DBZ)(1.7 nM), and a benzodiazepine (BZ)(2.2 nM). DBZ and BZ caused dose-dependent intestinal goblet cell metaplasia. In contrast, the AS produced no detectable in vivo toxicity despite higher exposure to free drug. In a time-course using BZ, small intestinal crypt and large intestinal glandular cell epithelial apoptosis was observed on days 1-5, followed by goblet cell metaplasia on days 2-5 and crypt epithelial and glandular epithelial regenerative hyperplasia on days 4-5. Gene expression profiling of duodenal samples from BZ-dosed animals revealed significant time-dependent deregulation of mRNAs for various panendocrine, hormonal and transcription factor genes. Somatostatin, secretin, mucin, CCK, and gastrin mRNAs were elevated two-fold or more by day 2 and a number of candidate "early-predictive" genes were altered on days 1-2, remaining changed for 4-5 days, and included Delta1, NeuroD, Hes1-regulated adipsin, and the Hes-regulated transcriptional activator of gut secretory lineage differentiation, the rat homologue of Drosophila atonal, Rath1. Western blotting of fecal protein from BZ-and DBZ-dosed animals exhibited increased levels of both anti-Rath1 reactive protein and anti-adipsin reactive proteins, confirming their potential value as non-invasive biomarkers of intestinal goblet metaplasia.-secretase; Notch receptor; NICD; intestinal goblet metaplasia; Rath1; Hes1; adipsin; atonal.
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