Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine.
Effect of Crohn's Disease on Villous Length and CYP3A4 Expression in the Pediatric Small Intestine.
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克罗恩病对小儿小肠绒毛长度和CYP3A4表达的影响
DOI：
10.1111/cts.12938
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Shakhnovich V
中科院分区：
文献类型：
--
作者：
Vyhlidal CA;Chapron BD;Ahmed A;Singh V;Casini R;Shakhnovich V
小肠吸收能力和首过代谢的变化影响口服药物的生物利用度。表征炎症引起的这些变化对于开发炎症性肠病的生理学药代动力学（PBPK）模型非常重要。我们试图阐明小肠克罗恩病（CD）对儿童绒毛长度和CYP 3A 4表达的影响。对107名患有和不患有CD的儿童（1-19岁）新鲜冷冻的十二指肠和末端回肠（TI）活检进行了活动性炎症评价。比较CD和对照组中活动性和非活动性炎症区域的绒毛长度和CYP 3A 4 mRNA/蛋白表达。在CD患儿发炎的尿道和伊利亚中观察到绒毛长度减少两倍，但在没有区域炎症的情况下，CD患儿的绒毛长度与对照组相当。CYP 3A 4 mRNA的表达与TI中的绒毛长度显著相关（P = 0.0003），在十二指肠中观察到的趋势未达到统计学显著性。在存在活动性炎症的情况下，证实了十二指肠中CYP 3A蛋白表达的显著降低，其中蛋白表达也与诊断中的绒毛长度显著相关（P < 0.0001）。我们的研究结果表明，先前观察到的炎症肠道中CYP 3A 4表达和功能降低可能不仅仅是由于炎症细胞因子的下调，还可能是由于绒毛钝化和随后蛋白表达表面积的损失。该信息与PBPK模型开发相关，并有助于CD发作期间口服CYP 3A 4底物给药的剂量调整决策（例如，布地奈德）。
Changes in absorptive capacity and first‐pass metabolism in the small intestine affect oral drug bioavailability. Characterization of such changes as a consequence of inflammation is important for developing physiologically‐based pharmacokinetic (PBPK) models for inflammatory bowel disease. We sought to elucidate the impact of small intestinal Crohn’s disease (CD) on villous length and CYP3A4 expression in children. Freshly frozen duodenal and terminal ileum (TI) biopsies from 107 children (1–19 years) with and without CD were evaluated for active inflammation. Villous length and CYP3A4 mRNA/protein expression were compared among regions of active and inactive inflammation in CD and controls. A twofold reduction in villous length was observed in inflamed duodena and ilia of children with CD, but in the absence of regional inflammation, villi in CD were comparable in length to controls. Expression of CYP3A4 mRNA correlated significantly with villous length in the TI (P = 0.0003), with a trend observed in the duodenum that did not reach statistical significance. In the presence of active inflammation, a significant decrease in CYP3A protein expression was confirmed in the duodenum, where protein expression also correlated significantly with villous length across diagnoses (P < 0.0001). Our findings suggest that previous observations of decreased CYP3A4 expression and function in inflamed intestine may not be due solely to downregulation by inflammatory cytokines, but also to villous blunting and subsequent loss of surface area for protein expression. This information is relevant for PBPK model development and could aid with dose adjustment decisions for oral CYP3A4 substrates administered during CD flare (e.g., budesonide).
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DOI：
10.1124/dmd.115.068742
发表时间：
2016-07
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Shakhnovich V;Vyhlidal C;Friesen C;Hildreth A;Singh V;Daniel J;Kearns GL;Leeder JS
通讯作者：
Leeder JS
影响因子：
4.3
作者：
Molnar, Tamas;Tiszlavicz, Laszlo;Lonovics, Janos
通讯作者：
Lonovics, Janos
影响因子：
4.3
作者：
Landy, Jonathan;Ronde, Emma;Al-Hassi, Hafid Omar
通讯作者：
Al-Hassi, Hafid Omar
影响因子：
9.8
作者：
Dubinsky, MC;Lin, YC;Yang, HY
通讯作者：
Yang, HY
DOI：
10.1124/jpet.108.149815
发表时间：
2009-08-01
影响因子：
3.5
作者：
Fan, Jianghong;Liu, Shanjun;Pang, K. Sandy
通讯作者：
Pang, K. Sandy