| First Author | Liu M | Year | 2016 |
| Journal | Biochem Pharmacol | Volume | 110-111 |
| Pages | 37-46 | PubMed ID | 27060662 |
| Mgi Jnum | J:235232 | Mgi Id | MGI:5795792 |
| Doi | 10.1016/j.bcp.2016.04.003 | Citation | Liu M, et al. (2016) Cadmium and arsenic override NF-kappaB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia. Biochem Pharmacol 110-111:37-46 |
| abstractText | Humanized UDP-glucuronosyltransferase (UGT)-1 (hUGT1) mice encode the UGT1 locus including the UGT1A1 gene. During neonatal development, delayed expression of the UGT1A1 gene leads to hyperbilirubinemia as determined by elevated levels of total serum bilirubin (TSB). We show in this report that the redox-sensitive NF-kappaB pathway is crucial for intestinal expression of the UGT1A1 gene and control of TSB levels. Targeted deletion of IKKbeta in intestinal epithelial cells (hUGT1/Ikkbeta(DeltaIEC) mice) leads to greater neonatal accumulation of TSB than observed in control hUGT1/Ikkbeta(F/F) mice. The elevation in TSB levels in hUGT1/Ikkbeta(DeltaIEC) mice correlates with a reduction in intestinal UGT1A1 expression. As TSB levels accumulate in hUGT1/Ikkbeta(DeltaIEC) mice during the neonatal period, the increase over that observed in hUGT1/Ikkbeta(F/F) mice leads to weight loss, seizures and eventually death. Bilirubin accumulates in brain tissue from hUGT1/Ikkbeta(DeltaIEC) mice inducing an inflammatory state as shown by elevated TNFalpha, IL-1beta and IL-6, all of which can be prevented by neonatal induction of hepatic or intestinal UGT1A1 and lowering of TSB levels. Altering the redox state of the intestines by oral administration of cadmium or arsenic to neonatal hUGT1/Ikkbeta(F/F) and hUGT1/Ikkbeta(DeltaIEC) mice leads to induction of UGT1A1 and a dramatic reduction in TSB levels. Microarray analysis following arsenic treatment confirms upregulation of oxidation-reduction processes and lipid metabolism, indicative of membrane repair or synthesis. Our findings indicate that the redox state in intestinal epithelial cells during development is important in maintaining UGT1A1 gene expression and control of TSB levels. |
