title: Cadmium and arsenic override NF-κB developmental regulation of the intestinal UGT1A1 gene and control of hyperbilirubinemia.
abstract: 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-κB pathway is crucial for intestinal expression of the UGT1A1 gene and control of TSB levels. Targeted deletion of IKKβ in intestinal epithelial cells (hUGT1/Ikkβ(ΔIEC) mice) leads to greater neonatal accumulation of TSB than observed in control hUGT1/Ikkβ(F/F) mice. The elevation in TSB levels in hUGT1/Ikkβ(ΔIEC) mice correlates with a reduction in intestinal UGT1A1 expression. As TSB levels accumulate in hUGT1/Ikkβ(ΔIEC) mice during the neonatal period, the increase over that observed in hUGT1/Ikkβ(F/F) mice leads to weight loss, seizures and eventually death. Bilirubin accumulates in brain tissue from hUGT1/Ikkβ(ΔIEC) mice inducing an inflammatory state as shown by elevated TNFα, IL-1β 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/Ikkβ(F/F) and hUGT1/Ikkβ(ΔIEC) 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.
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States; State Key Laboratory of Natural Medicine, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Miao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States.
authors.forename: Mei-Fei
authors.initials: MF
authors.lastname: Yueh
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States.
authors.forename: Camille
authors.initials: C
authors.lastname: Konopnicki
authors.affiliation: State Key Laboratory of Natural Medicine, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, People's Republic of China.
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.affiliation: Laboratory of Environmental Toxicology, Departments of Chemistry & Biochemistry and Pharmacology, University of California, San Diego, La Jolla, CA 92023, United States. Electronic address: rtukey@ucsd.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001151:Arsenic / Q000494:pharmacology*; D001663:Bilirubin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002104:Cadmium / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006932:Hyperbilirubinemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012640:Seizures / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects; D000099148:UGT1A1 Enzyme
chemical_list: D001151:Arsenic; D001663:Bilirubin; D002104:Cadmium; D014453:Glucuronosyltransferase; D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000099148:UGT1A1 Enzyme; C587672:IL1B protein, mouse; C577686:interleukin-6, mouse
keywords: Bilirubin; Humanized UGT1 mice; Inflammation; Intestinal IKKβ; Oxidative stress; UDP-glucuronosyltransferase 1A1