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.

Dietary Dihydromethysticin Increases Glucuronidation of 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanol in A/J Mice, Potentially Enhancing Its Detoxification

“…These results overall support the mechanism that dietary DHM treatment enhances NNAL glucuronidation both in the lung and liver tissues, which may lead to increased NNAL detoxification and reduction in NNAL-derived DNA damage in A/J mice. Dietary DHM may up-regulate UGT enzyme(s) via transcriptional activation of AHR as DHM is a potential AHR agonist (Li et al, 2011) and AHR can transcriptionally activate UGTs (Bock and Bock-Hennig, 2010).…”

“…After 15 minutes of incubation at 37°C, the reaction was terminated with the addition of 20 ml of trifluoroacetic acid (15%). The formation of 7-hydroxycoumarin from coumarin was measured by high-pressure liquid chromatography with fluorescence detection as previously described elsewhere (Bock and Bock-Hennig, 2010).…”

Focused DNA microarray analysis for sex-dependent gene expression of drug metabolizing enzymes, transporters and nuclear receptors in rat livers and kidneys

“…The female dominant expressions of UDP glucuronosyltransferase (UGT) s and aryl hydrocarbon receptor (AhR) are observed in adult rat livers and kidneys. The gene expressions of UGT1 family were reported to be regulated by AhR (Bock and Bock-Hennig, 2010). Together with these results, it may be possible that the sex-divergent gene expressions of UGTs are caused by the female dominant expression of AhR.…”

UDP-glucuronosyltransferase 1A6 overexpression in breast cancer cells resistant to methotrexate

“…TCDD (dioxin) is one of the compounds that induce UGT1A6 via AhR binding to the XRE as it has been observed in primary hepatocyte cultures and in colon carcinoma Caco-2 cells [14]. Some AhR agonists cause coordinate induction of both phase-I CYPs and UGTs to attenuate the generation of mutagenic benzo[a]pyrene metabolites, facilitating detoxification of the carcinogen [52]. In addition, UGTs may be responsible for homeostatic control of AhR ligands, such as bilirubin [52].…”

“…Some AhR agonists cause coordinate induction of both phase-I CYPs and UGTs to attenuate the generation of mutagenic benzo[a]pyrene metabolites, facilitating detoxification of the carcinogen [52]. In addition, UGTs may be responsible for homeostatic control of AhR ligands, such as bilirubin [52]. AhR can also induce UGT1A6 expression through Nrf2 binding to the ARE element present in the UGT1A6 promoter [43], however no induction in response to MTX was observed in the luciferase assays for the first 1000 bp region , where the ARE site is located.…”