Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene

Lankisch, Tim O.; Gillman, T.C.; Erichsen, Thomas; Ehmer, Ursula; Kalthoff, Sandra; Freiberg, N.; Münzel, Peter A.; Manns, Michael P.; Strassburg, Christian P.

doi:10.1007/s00204-008-0347-1

Cited by 40 publications

(28 citation statements)

References 33 publications

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“…HepG2 cells were transfected for dual luciferase assays as previously reported [30]. In addition, hepatoma cells expressing sodium taurocholate cotransporting polypeptide (NTCP), that have been previously characterized and described by Rust et al, were used in additional experiments to account for the lack of ntcp expression in HepG2 cells [32].…”

Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

“…Sequences of EMSA oligonucleotides are shown in Table 1B. The samples were electrophoretically separated and visualized as described elsewhere [30]. EMSA supershift assays were performed by incubation with 2 lg of anti-FXR-antibody or anti-RXRa-antibody (both Santa Cruz, Santa…”

Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

“…BA were quantitated by photometric analysis in the clinical chemistry routine laboratory of Hannover Medical School, bile was added to HepG2 cell cultures to a concentration of 100 lM total bile acids 24 h following transfection, and cells were harvested 48 h after induction. Luciferase activity was measured as previously reported [30]. All experiments were performed in at least triplicate.…”

Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

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Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids

Erichsen

Aehlen

Ehmer

et al. 2010

Journal of Hepatology

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Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

Section: Luciferase Reporter Gene Experimentsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids

Erichsen

Aehlen

Ehmer

et al. 2010

Journal of Hepatology

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“…UGT1A3 efficiently catalyzes the glucuronidation of endogenous substances, such as estrogen and bile acids, and inhibition of UGT1A3 activity may disrupt the metabolism of these compounds. 26) UGT2B7 can also conjugate endogenous substances, including bile acids, androgens, and estrogens. 27) Many compounds have been reported to inhibit UGT2B7, such as arbidol and herbal andrographolide derivatives.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Liú

Xie

et al. 2016

Biological & Pharmaceutical Bulletin

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Hesperetin (HET) and naringenin (NGR) are flavanones found in citrus (oranges and grapefruit) andAurantii Fructus Immaturus. The present study aims to investigate the inhibition potential of HET and NGR derivatives towards one of the most important phase II drug-metabolizing enzymes-uridine diphosphate (UDP)-glucuronosyltransferases (UGTs). We used trifluoperazine as a probe substrate to test UGT1A4 activity, and recombinant UGT-catalyzed 4-methylumbelliferone glucuronidation was used as a probe reaction for other UGT isoforms. Data show that HET and NGR displayed broad-spectrum inhibition against human UGTs. Besides, HET exhibited strong inhibitory effects on UGT1A1, 1A3 and 1A9 (both IC 50 and K i values lower than 10 µM), and the inhibitory effects of NGR against three major UGTs, including UGT1A1, 1A3 and 2B7. In a combination of inhibition parameters (K i ) and in vivo concentration of HET and NGR, the potential in vivo inhibition magnitude was predicted. Based on the reported maximum plasma concentration of HET and NGR in vivo, these findings indicate the potential herb-drug interactions (HDI) between HET or NGR and the drugs mainly undergoing UGT1A3 or UGT2B7 catalyzed metabolic elimination. Considering the variety of citrus that contains HET and NGR, so caution should be applied when taking drugs that utilize UGTs for metabolism and clearance with citrus fruits. Key words herb-drug interaction; hesperetin; naringenin; uridine diphosphate (UDP)-glucuronosyltransferaseHesperetin (HET; 4′-methoxy-3′,5,7-trihydroxyflavanone) and naringenin (NGR; 4,5,7-trihydroxyflavanone), aglycones of the flavanone glycoside hesperidin (chiefly in oranges) and naringin (grapefruits) are also used as dietary flavonoids. 1)Moreover, flavanones are bioactive components of Aurantii Fructus Immaturus, which is reported to be used in traditional Chinese medicine.2) Several animal studies have been performed to document pharmacokinetics of HET and NGR. 3,4) The role of HET and NGR in the treatment of disease has received considerable attention, and it is reported to have antioxidant, anti-inflammatory, anti-hypertensive, anti-atherogenic, anti-diabetic, antiviral, and neuroprotective activities. 5-8)Thus, HET and NGR have multiple uses and pharmacokinetic studies of both compounds may elucidate information about efficacy and safety. Chemical structures of HET and NGR appear in Fig. 1.Herb-drug interaction (HDI) strongly limits the clinical application of herbs and drugs, and the inhibition of herbal components towards important drug-metabolizing enzymes (DMEs) has been regarded as one of the most important reasons.9) CYP450 and uridine diphosphate (UDP)-glucuronosyltransferase (UGT) are two enzymes responsible for oxidative phase I and conjugative phase II reactions, respectively. 10) In the past decades, the CYP450 inhibition by HET and NGR has been widely studied, the effects of HET and NGR on UGTs activity have not been fully characterized. Moreover, a large number of different UGTs that exhibit a wide range of substrates are...

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“…The wild-type clones for splice variants HNF4␣1, HNF4␣2 (the most abundant transcript in adult human liver), and HNF4␣7 were chosen for transfection experiments. The HNF1␣ expression vector has been described previously (Lankisch et al, 2008a). DNA concentrations were determined by spectrophotometry at 260 nm.…”

Section: Methodsmentioning

confidence: 99%

Shared Regulation of UGT1A7 by Hepatocyte Nuclear Factor (HNF) 1α and HNF4α

Ehmer

Kalthoff²,

Lankisch³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Substrates for glucuronidation include endogenous and xenobiotic compounds such as environmental carcinogens and drugs, as well as the chemotherapeutic agent irinotecan. The UDP-glucuronosyltransferase (UGT) 1A7 gene is expressed in the upper gastrointestinal tract and the lung but is not expressed in the liver. The transcriptional regulation of UGT1A7 and the putative influence of single nucleotide polymorphisms (SNPs) are incompletely characterized. UGT1A8, UGT1A9, and UGT1A10, which are highly homologous to UGT1A7, have been reported to be transcriptionally regulated by hepatocyte nuclear factors (HNFs). In this study, we show the activation of UGT1A7 by the aforementioned transcription factors. Sequence analyses, mutagenesis, reporter gene experiments, small interfering RNA silencing, chromatin immunoprecipitation, and electromobility shift assays identified five HNF binding sites in the proximal promoter region of UGT1A7 that were regulated by HNF1␣ and HNF4␣. Activation by HNF1␣ was lower in the presence of the UGT1A7 ؊57G SNP. In contrast to liver-expressed UGT1A9, transcriptional activation of UGT1A7 by HNF4␣ was lower and dependent on higher HNF4␣ concentrations, which may contribute to the observed differences in tissue expression patterns. Therefore, a specific role of HNF in the transcriptional control of UGT1A7 is shown and characterized, which may contribute to its tissue specificity and function.

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Aryl hydrocarbon receptor-mediated regulation of the human estrogen and bile acid UDP-glucuronosyltransferase 1A3 gene

Cited by 40 publications

References 33 publications

Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids

Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids

Inhibitory Effect of Hesperetin and Naringenin on Human UDP-Glucuronosyltransferase Enzymes: Implications for Herb–Drug Interactions

Shared Regulation of UGT1A7 by Hepatocyte Nuclear Factor (HNF) 1α and HNF4α

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