RESUMO
Microsomal epoxide hydrolase (mEH) is a bifunctional protein that plays a central role in carcinogen metabolism and is also able to mediate the sodium-dependent uptake of bile acids into hepatocytes. Studies have identified a subject (S-1) with extremely elevated serum bile salt levels in the absence of observable hepatocellular injury, suggesting a defect in bile acid uptake. In this individual, mEH protein and mEH mRNA levels were reduced by approximately 95% and 85%, respectively, whereas the expression and amino acid sequence of another bile acid transport protein (NTCP) was unaffected. Sequence analysis of the mEH gene (EPHX1) revealed a point mutation at an upstream HNF-3 site (allele I) and in intron 1 (allele II), which resulted in a significant decrease in EPHX1 promoter activity in transient transfection assays. Gel shift assays using a radiolabeled oligonucleotide from each region resulted in specific transcription factor binding patterns, which were altered in the presence of the mutation. These studies demonstrate that the expression of mEH is greatly reduced in a patient with hypercholanemia, suggesting that mEH participates in sodium-dependent bile acid uptake in human liver where its absence may contribute to the etiology of this disease.
Assuntos
Ácidos e Sais Biliares/metabolismo , Colanos/sangue , Epóxido Hidrolases/metabolismo , Fígado/enzimologia , Mutação Puntual , Alelos , Sítios de Ligação , Northern Blotting , Western Blotting , Proteínas de Ligação a DNA/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Epóxido Hidrolases/análise , Epóxido Hidrolases/genética , Regulação da Expressão Gênica , Genótipo , Fator 3-beta Nuclear de Hepatócito , Humanos , Íntrons , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/análise , Fatores de Transcrição/metabolismoRESUMO
After the intake of approximately 24 g wheat bran daily for 5 weeks, 25 trainee nurses showed no changes in the serum levels of cholesterol, triglyceride, calcium or total 3 alpha-hydroxycholanic acid. On the other hand, the study revealed a reduced intestinal transit time with good correlation to an increased frequency of bowel movements. Average body weight fell significantly, by 0.4 kg. The daily caloric intake remained constant throughout the study period, whereas the calcium intake was significantly increased. Among the serum parameters and the dietary constituents, good correlation was found only between serum cholesterol and the dietary cholesterol content. In addition, an inverse relationship was demonstrated between the serum levels of cholesterol and total 3 alpha-hydroxycholanic acid. The significance of this observation is as yet unknown.
