DEFECTIVE BILE ACID SYNTHESIS IN CHILDHOOD CONSTIPATION

儿童便秘的胆汁酸合成缺陷

• 批准号: 6931906
• 负责人: ALAN F HOFMANN
• 金额: $ 15.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6931906
• 关键词: chemical structure function; child (0-11); cholanate compound; clinical research; constipation; cytochrome P450; disease /disorder etiology; disease /disorder proneness /risk; enzyme deficiency; enzymes; feces analysis; genetic polymorphism; high performance liquid chromatography; human genetic material tag; human subject; laxative; liver disorder; mass spectrometry; oxygenases; patient oriented research; pediatrics; peroxisome; steroid biosynthesis

DESCRIPTION (provided by applicant): Constipation in children is a common, vexing problem for the patient, his or her parents, and the pediatric gastroenterologist. Most cases have no discernible organic cause. Evidence indicates that endogenous C24 dihydroxy- bile acids (chenodeoxycholic and/or deoxycholic acid) act as natural cathartics by inducing colonic secretion and colonic propulsion. Our hypothesis is that some cases of childhood constipation are caused by defects in bile acid biosynthesis resulting in a decreased colonic concentration of C24 dihydroxy bile acids. Possible defects include defective hydroxylation of the steroid nucleus (defective sterol 12 hydroxylase (cyp8B1) or defective side chain oxidation (defects in peroxisomal enzymes). To test this hypothesis, fecal samples will be obtained from children with chronic constipation as well as from children without constipation. Samples will be analyzed by electrospray mass spectrometry (ESI-MS) and by gas chromatography mass spectrometry (GC-MS). ESI-MS provides information on side chain biotransformations involved in oxidation of the C8 cholesterol side chain to the C5 side chain present in C24 bile acids. GC-MS provides information on the efficiency of C-12 hydroxylation. Patients with defects in side chain oxidation or C-12-hydroxylation will receive genetic analysis by collaborators. If successful, this project will show that some cases of constipation are caused by defective bile acid biosynthesis.Preliminary results have identified children with increased C27 bile acids suggesting defects in peroxisomal enzymes. Results of this study should lead to clinical trials that test the efficacy of oral primary bile acids for constipation caused by defective bile acid biosynthesis.

描述（由申请人提供）： 儿童便秘是患者，他或她的父母和小儿胃肠病医生的常见问题。大多数情况没有明显的有机原因。有证据表明，内源性C24二羟基胆汁酸（Chendoxycholic和/或脱氧胆酸）通过诱导结肠分泌和结肠推进来起到天然宣泄作用。我们的假设是，某些儿童便秘病例是由胆汁酸生物合成的缺陷引起的，导致C24二羟基胆汁酸的结肠浓度降低。可能的缺损包括类固醇核的缺陷羟基化（有缺陷的固醇12羟化酶（CYP8B1）或有缺陷的侧链氧化（过氧化物酶体酶缺陷）。为了检验该假说，将通过慢性病儿童以及群群的儿童获得粪便样本。 （ESI-MS）和气体色谱质谱法（GC-MS）提供有关C8胆固醇侧链氧化的侧链生物转化的信息。通过合作者。这项研究的结果应导致临床试验测试口服原发性胆汁酸的功效，该胆汁酸对胆汁酸生物合成有缺陷引起的便秘。

项目成果

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culprit.

9 号染色体上的两个基因座控制胆汁酸的组成：证据表明强大的候选基因 Cyp8b1 并不是罪魁祸首。

• DOI: 10.1194/jlr.m600176-jlr200
• 发表时间: 2006
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Sehayek,Ephraim;Hagey,LeeR;Fung,Yee-Yan;Duncan,ElizabethM;Yu,HannahJ;Eggertsen,Gösta;Björkhem,Ingemar;Hofmann,AlanF;Breslow,JanL
• 通讯作者: Breslow,JanL

Physiological concentrations of bile acids down-regulate agonist induced secretion in colonic epithelial cells.

胆汁酸的生理浓度下调激动剂诱导的结肠上皮细胞分泌。

• DOI: 10.1111/j.1582-4934.2009.00838.x
• 发表时间: 2009
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Keating,Niamh;Mroz,MagdalenaS;Scharl,MichaelM;Marsh,Christine;Ferguson,Gail;Hofmann,AlanF;Keely,StephenJ
• 通讯作者: Keely,StephenJ

Diversity of bile salts in fish and amphibians: evolution of a complex biochemical pathway.

• DOI: 10.1086/649966
• 发表时间: 2010-03
• 期刊: Physiological and biochemical zoology : PBZ
• 作者: Hagey LR;Møller PR;Hofmann AF;Krasowski MD
• 通讯作者: Krasowski MD