Genetic variability of aryl hydrocarbon receptor (AhR)-mediated regulation of the human UDP glucuronosyltransferase (UGT) 1A4 gene

Journal Article · Tue Jul 15 00:00:00 EDT 2008 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2008.02.020· OSTI ID:21140900

Erichsen, Thomas J; Ehmer, Ursula; Kalthoff, Sandra; Lankisch, Tim O; Mueller, Tordis M ^[1]; Munzel, Peter A ^[2]; Manns, Michael P ^[1]

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1. Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Medical School, Hannover (Germany)
2. Department of Toxicology, Institute of Pharmacology and Toxicology, University of Tubingen, Tubingen (Germany)

UDP glucuronosyltransferases (UGTs) play an important role for drug detoxification and toxicity. UGT function is genetically modulated by single nucleotide polymorphisms (SNPs) which lead to the expression of functionally altered protein, or altered expression levels. UGT1A4 activity includes anticonvulsants, antidepressants and environmental mutagens. In this study the induction of the human UGT1A4 gene and a potential influence of genetic variation in its promoter region were analyzed. SNPs at bp - 219 and - 163 occurred in 9% among 109 blood donors reducing UGT1A4 transcription by 40%. UGT1A4 transcription was dioxin inducible. Reporter gene experiments identified 2 xenobiotic response elements (XRE), which were functionally confirmed by mutagenesis analyses, and binding was demonstrated by electromobility shift assays. Constitutive human UGT1A4 gene expression and induction was aryl hydrocarbon receptor (AhR)-dependent, and reduced in the presence of SNPs at bp - 219 and - 163. AhR-mediated regulation of the human UGT1A4 gene by two XRE and a modulation by naturally occurring genetic variability by SNPs is demonstrated, which indicates gene-environment interaction with potential relevance for drug metabolism.

• OSTI ID: 21140900
• Journal Information: Toxicology and Applied Pharmacology, Vol. 230, Issue 2; Other Information: DOI: 10.1016/j.taap.2008.02.020; PII: S0041-008X(08)00097-5; Copyright (c) 2008 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTICONVULSANTS
ANTIDEPRESSANTS
BLOOD
DETOXIFICATION
DIOXIN
ENVIRONMENTAL EXPOSURE
GENES
GENETIC VARIABILITY
HYDROCARBONS
METABOLISM
MODULATION
MUTAGENESIS
MUTAGENS
NUCLEOTIDES
PROMOTERS
RECEPTORS
REGULATIONS
TOXICITY
TRANSCRIPTION