The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics

Sugatani, Junko; Yamakawa, Kasumi; Tonda, Eri; Nishitani, Shinichi; Yoshinari, Kouichi; Degawa, Masakuni; Abe, Ikuro; Noguchi, Hiroshi; Miwa, Masao

doi:10.1016/j.bcp.2003.11.002

Cited by 108 publications

(84 citation statements)

References 32 publications

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“…Instead, UGT1A1 may be the primary UGT involved in N-OH-PhIP glucuronidation (43). Another possible explanation for the contrasting joint effects is that the UGTs are differentially inducible by other dietary compounds, such as flavonoids (44,45), which may effect expression of the individual isozymes.…”

Section: Discussionmentioning

confidence: 99%

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Butler

Duguay

Millikan³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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The UDP-glucuronosyltransferase 1A7 (UGT1A7) gene is polymorphic and encodes an enzyme involved in the detoxification of heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Consumption of pan-fried and well-done meat are surrogates for HCA and PAH exposure and are possibly associated with colon cancer. We have evaluated whether UGT1A7 allelic variations are associated with colon cancer and whether UGT1A7 genotype modified associations among meat intake, exposure to HCAs and PAHs, and colon cancer in a population-based case-control study of African Americans (197 cases and 202 controls) and whites (203 cases and 210 controls). As part of a 150-item food frequency questionnaire, meat intake was assessed by cooking method and doneness and used to estimate individual HCA and PAH exposure. UGT1A7 alleles (UGT1A7*1, UGT1A7*2, UGT1A7*3, and UGT1A7*4) were measured and genotypes were categorized into predicted activity groups (high: *1/*1, *1/*2, *2/*2; intermediate: *1/*3, *1/*4, *2/*3; low: *3/*3, *3/*4, *4/*4). There was no association with UGT1A7 low versus high/intermediate genotype [odds ratio (OR), 1.1; 95% confidence interval (95% CI), 0.7-1.8], regardless of race. Greater than additive joint effects were observed for UGT1A7 low genotype and HCA-related factors. For example, equal to or greater than the median daily intake of the HCA,4,

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Section: Discussionmentioning

confidence: 99%

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Butler

Duguay

Millikan³

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…However, PXR and CAR were also shown to contribute to the overall UGT1A1 response to flavonoids [70]. ↑ luciferase activity ↑ CAT activity for α and γ Effective binding to PXR ↑ CYP3A4, no effect on UGT1A1 or MDR-1 ↑ MDR-1, ↑ UGT1A1, no effect on CYP3A4 ↑ CYP3A4/3A5 by γ Zhou et al [62] Landes et al [63] Zhou et al [62] Zhou et al [62] Zhou et al [62] Landes et al [63] Vitamin E CYP3A4 cell-based reporter assay with PXR α-, β-, γ-, and δ-tocopherols Ligand-binding assay PXR Mu et al [68] Abbreviations: AUC, area under the concentration-time curve; CAT, chloramphenicol acetyltransferase reporter gene activity; CYP, cytochrome P450; C max , maximum observed concentration; MDR, multidrug resistance gene; MRP, multidrug resistanceassociated protein; PXR, pregnane X receptor; t 1/2 , half-life; TCM, traditional Chinese medicine; UGT, uridine diphosphoglucuronosyl transferase.…”

Section: In Vitromentioning

confidence: 99%

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

2006

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An increasing number of cancer patients are using complementary and alternative medicines (CAM) in combination with their conventional chemotherapeutic treatment. Considering the narrow therapeutic window of oncolytic drugs, this CAM use increases the risk of clinically relevant herb-anticancer drug interactions. Such a relevant interaction is that of St. John's wort with the anticancer drugs irinotecan and imatinib. It is, however, estimated that CAM-anticancer drug interactions are responsible for substantially more unexpected toxicities of chemotherapeutic drugs and possible undertreatment seen in cancer patients.Induction of drug-metabolizing enzymes and ATP-binding cassette drug transporters can be one of the mechanisms behind CAM-anticancer drug interactions. Induction will often lead to therapeutic failure because of lower plasma levels of the anticancer drugs, and will easily go unrecognized in cancer treatment, where therapeutic failure is common.Recently identified nuclear receptors, such as the pregnane X receptor, the constitutive androstane receptor, and the vitamin D-binding receptor, play an important role in the induction of metabolizing enzymes and drug transporters. This knowledge has already been an aid in the identification of some CAM probably capable of causing interactions with anticancer drugs: kavakava, vitamin E, quercetin, ginseng, garlic, β-carotene, and echinacea. Evidently, more research is necessary to prevent therapeutic failure and toxicity in cancer patients and to establish guidelines for CAM use. The Oncologist 2006;11:742-752 Learning ObjectivesAfter completing this course, the reader will be able to:1. Describe the possible pharmacokinetic interactions between complementary alternative medicines and oncolytic drugs and the clinical consequences thereof.2. Define the role of the nuclear receptors PXR, CAR, and VDR in herb-drug interactions.3. Discuss methods to measure induction of drug-metabolizing enzymes and transporters.Access and take the CME test online and receive 1 AMA PRA Category 1 Credit

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“…UGT1A1, plays a critical role in the detoxification of potentially neurotoxic bilirubin by conjugating it with glucuronic acid for excretion in bile (Ostrow and Murphy, 1970) and also conjugates drugs and other xenobiotics (Radominska-Pandya et al, 1999;Tukey and Strassburg, 2000). We identified the gtNR1 motif (-3382/-3367), which plays a central role in the expression of UGT1A1 and is mediated by both hCAR and hPXR (Sugatani et al, 2001(Sugatani et al, , 2004(Sugatani et al, , 2005a(Sugatani et al, ,b, 2008. Thus, in the present study, CYP3A4 and UGT1A1 were used as biomarkers of exogenously expressed hPXR activation.…”

Section: Introductionmentioning

confidence: 99%

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca²⁺/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

et al. 2014

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The human pregnane X receptor (hPXR) is recognized as a xenobioticsensing nuclear receptor that transcriptionally regulates the gene expression of drug-metabolizing enzymes and transporters. Our study elucidates the mechanism by which the localization of hPXR is regulated through threonine-290. A phosphomimetic mutation at threonine-290 (T290D) retained hPXR in the cytoplasm of HepG2, HuH6, and SW480 cells in vitro and the mouse liver in vivo even after treatment with rifampicin, and a phosphodeficient mutation (T290A) translocated from the cytoplasm to the nucleus as the wild-type hPXR. The amount of the unphosphorylated wild-type yellow fluorescent protein-hPXR fusion protein but not the T290A mutant increased on Phos-tag gels in response to stimulations with rifampicin and cyclin-dependent kinase 2 inhibitor roscovitine, and a marked increase was observed in the unphosphorylated levels of the T290A mutant in nontreated cells. The Ca CaMKII directly phosphorylated the threonine-290 of hPXR, and the T290A mutant conferred resistance to CaMKII. The protein phosphatase (PP) inhibitor okadaic acid (100 nM) and transfection with anti-PP1 siRNA but not anti-PP2A siRNA led to reduced expression of CYP3A4 mRNA. After the rifampicin and roscovitine stimulations, PP1 was recruited to the wild-type hPXR but not the T290A mutant. These results suggest that phosphorylation at threonine-290 by CaMKII may impair the function of hPXR by repressing its translocation to the nucleus, and dephosphorylation by PP1 is necessary for the xenobiotic-dependent nuclear translocation of hPXR.

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The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics

Cited by 108 publications

References 32 publications

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca²⁺/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

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The induction of human UDP-glucuronosyltransferase 1A1 mediated through a distal enhancer module by flavonoids and xenobiotics

Cited by 108 publications

References 32 publications

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Joint Effects between UDP-Glucuronosyltransferase 1A7 Genotype and Dietary Carcinogen Exposure on Risk of Colon Cancer

Herb–Drug Interactions in Oncology: Focus on Mechanisms of Induction

Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca2+/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1

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Threonine-290 Regulates Nuclear Translocation of the Human Pregnane X Receptor through Its Phosphorylation/Dephosphorylation by Ca²⁺/Calmodulin-Dependent Protein Kinase II and Protein Phosphatase 1