UDP-glucuronosyltransferases (UGTs): from purification of Ah-receptor–inducible UGT1A6 to coordinate regulation of subsets of CYPs, UGTs, and ABC transporters by nuclear receptors

Abstract

Differential induction of rat-liver microsomal uridine diphospho-glucuronosyltransferase (UGT) activities by 3-methylcholanthrene or phenobarbital provided the model to separate and purify the corresponding UGT enzymes, initially termed GT1 and GT2, respectively. Characterization of these enzymes helpful in the sequencing of the first inducible UGTs, now termed UGT1A6 and UGT2B1, may be considered the founding members of the current two evolutionarily conserved UGT families. Comparison of hepatic UGT1A6 induction by Ah-receptor (AhR) ligands in different species revealed low basal expression and high induction in rodents but high constitutive expression and moderate induction in humans. Induction of UGT1A6 by AhR was studied in the Caco-2 human colon carcinoma cell line. Similar to the induction of cytochrome-1 (CYP1) enzymes, the induction of human UGT1A6 was due to the binding of AhR to a common binding motif, a xenobiotic response element (XRE) in the promoter/enhancer region of the gene. Coordinate induction of CYPs and UGTs attenuates the generation of mutagenic benzo[a]pyrene metabolites, facilitating detoxification of the carcinogen. In addition and similar to observations with CYPs, UGTs may be responsible for homeostatic control of AhR ligands, such as bilirubin, a fruitful area to be studied in the future.

Keywords::

• UDP-glucuronosyltransferases
• CYPs
• Ah receptor
• CAR
• PXR

Acknowledgments

The authors are very grateful to many students and postdocs, in particular to Dr. Christoph Köhle (PhD, Department of Toxicology, University of Tübingen); successful research cannot be carried out without dedicated collaborators. The authors apologize for often quoting reviews instead of original investigations. This was done to reduce the number of references.

Declaration of interest: Our work was supported by grants of the Deutsche Forschungsgemein schaft, Bonn, Germany.