Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation

被引:448
作者
Milano, J
McKay, J
Dagenais, C
Foster-Brown, L
Pognan, F
Gadient, R
Jacobs, RT
Zacco, A
Greenberg, B
Ciaccio, PJ
机构
[1] AstraZeneca, Mol & Invest Toxicol, Safety Assessment US, Wilmington, DE 19850 USA
[2] AstraZeneca, DMPK, Wilmington, DE 19850 USA
[3] AstraZeneca, Neurosci, Wilmington, DE 19850 USA
[4] AstraZeneca, Target Biol, Wilmington, DE 19850 USA
[5] AstraZeneca, Chem, Wilmington, DE 19850 USA
[6] AstraZeneca, Safety Assessment UK, Macclesfield SK10 4TG, Cheshire, England
关键词
gamma-secretase; Notch receptor; Notch intracellular domain; NICD; intestinal goblet metaplasia; Rath1; Hes1; adipsin; atonal;
D O I
10.1093/toxsci/kfh254
中图分类号
R99 [毒物学(毒理学)];
学科分类号
100405 ;
摘要
It is anticipated that gamma-secretase inhibitors (gamma-Sec-I) that 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 mumol/kg b.i.d. gamma-Sec-I from three 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). The 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 cell 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 twofold 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; these included Delta1, NeuroD, Hes1-regulated adipsin, and the Hes-regulated transcriptional activator of gut secretory lineage differentiation, the rat homolog 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 noninvasive biomarkers of intestinal goblet metaplasia.
引用
收藏
页码:341 / 358
页数:18
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