The human UDP-glucuronsyltransferases (UGTs) are responsible for the metabolism of many endogenous and exogenous compounds. They facilitate excretion by attaching glucuronic acid to a lipophilic parent compound, transforming it to a more water-soluble glucuronide that can be easily eliminated.
Experiments performed in recombinant systems have suggested that protein-protein interactions occur between the UGTs and may play a role in modulating activity. However, evidence of UGT interactions either in vivo or in more physiologically relevant in vitro systems has yet to be demonstrated. UGT oligomerization and its ability to affect glucuronidation were examined by siRNA knockdown and activity studies. Selective down regulation of UGT1A9 or UGT2B7 resulted in significant decreases in their respective mRNA levels. As expected, metabolism of the UGT1A9 probe substrate propofol was abolished with UGT1A9 down regulation. UGT1A9 activity also decreased with UGT2B7 down regulation, implying potential interactions between two isoforms. This represents the first piece of evidence that UGT interactions occur in human hepatocytes and suggests that expression levels of UGT2B7 may directly impact glucuronidation of selective UGT1A9 substrates.
UGT1A1 is one of the most important UGTs because it is the primary UGT responsible for bilirubin metabolism. The UGT1A1 gene is also regulated by almost all of the xenobiotic receptors. We have recently generated a humanized UGT1 mouse model that exhibits elevated bilirubin levels during development. Since numerous toxicants induce UGT1A1 through association with xenobiotic receptors, UGT1A1 induction by environmental contaminants can alter hUGT1 bilirubin levels, therefore serving as a sensor for toxicant exposure. We investigated association between prominent metal contaminant exposure and UGT1A1 expression through fluctuations in bilirubin. Arsenic exposure reduced bilirubin in neonatal hUGT1 mice and significantly induced intestinal UGT1A1. The prevalence of arsenic contamination throughout the world fueled investigation into the regulatory role of oral arsenic on UGT1A1 expression. Q-PCR, Western Blot, and immunohistological analysis revealed a novel mechanism that implicates Nrf2, NF-κB and cellular proliferation as potential underlying regulators of arsenic-induced UGT1A1 expression in hUGT1 mice.
|Advisor:||Tukey, Robert H.|
|Commitee:||Dorrestein, Pieter, Halpert, James, Hoffmann, Alexander, Trogler, William|
|School:||University of California, San Diego|
|School Location:||United States -- California|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pharmacology, Biochemistry|
|Keywords:||Arsenic exposure, Bilirubin, Dimerization, Drug metabolism, Glucuronidation, UDP-glucuronosyltransferase|
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