Induction of Drug Metabolism: The Role of Nuclear Receptors

Handschin, Christoph; Meyer, Urs

doi:10.1124/pr.55.4.2

Cited by 409 publications

(147 citation statements)

References 274 publications

(310 reference statements)

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“…2,3) We thus also determined hepatic mRNA and nuclear protein levels of liver-enriched nuclear receptors including CAR, PXR, PPARa, PPARg, RXRa and HNF-4a. Quantitative RT-PCR analyses demonstrated that mRNA levels of PXR, RXRa and PPARg in saline-or PB-treated db/db mice were significantly higher than those in corresponding C57 mice (Fig.…”

Section: Genementioning

confidence: 99%

“…In rodent livers prototypes of P450 inducers, phenobarbital (PB) and dexamethasone, activate CAR and PXR, respectively, and the activated receptors form a heterodimer with retinoid X receptor (RXR) and transcriptionally activate the expression of CYP2B and CYP3A genes. 2,3) Another member of the nuclear receptor superfamily, peroxisome proliferator-activated receptor a (PPARa), mediates CYP4A induction by fibrates as a heterodimer with RXR. 2) Physiological and pathophysiological conditions also affect the activity of P450s and other enzymes.…”

mentioning

confidence: 99%

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Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Yoshinari

Takagi

Sugatani

et al. 2006

Biological & Pharmaceutical Bulletin

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Physiological and pathophysiological conditions often affect the expression of drug metabolizing enzymes such as cytochromes P450 (P450s). Diabetes is one such factor and it is of great interest to understand its effects on drug metabolism, since diabetic patients generally have increased need for pharmacotherapy. We have recently reported the coordinated reduction of CYP2B1/2 and their transcriptional regulator constitutive androstane receptor (CAR), a member of the nuclear receptor superfamily, in the liver of genetically obese/diabetic Zucker fatty rats (Xiong, H., Yoshinari, K., et al., Drug Metab. Dispos., 30, 918-923, 2002). In this study, we investigated the expression of P450s and liver-enriched nuclear receptors in the liver of genetically diabetic db/db mice. Surprisingly, both CYP2B10 and CAR levels were increased in db/db mice. CYP4A expression was also increased at both mRNA and protein levels in db/db mice, while those of peroxisome proliferator-activated receptor a a, a key regulator for the transcriptional activation of CYP4As, were comparable to those in age-matched C57BL/6 mice. Our results demonstrate that db/db mice and Zucker fatty rats exhibit different expression profiles of P450s and nuclear receptors despite their similar characteristics for obesity and diabetes resulting from a defect in the leptin signaling pathway.

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Section: Genementioning

confidence: 99%

mentioning

confidence: 99%

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Yoshinari

Takagi

Sugatani

et al. 2006

Biological & Pharmaceutical Bulletin

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“…CAR, upon activation by therapeutics such as PB, induces a large set of genes that encode for drugmetabolizing enzymes with the CYP2B enzymes being the classic CAR-regulated genes, thus increasing hepatic capability for drug metabolism and excretion (2)(3)(4). CAR plays the essential role in PB-induced promotion of hepatocellular carcinoma development (5).…”

mentioning

confidence: 99%

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

Mutoh

Osabe

Inoue

et al. 2009

Journal of Biological Chemistry

121

136

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Upon activation by therapeutics, the nuclear xenobiotic/ constitutive active/androstane receptor (CAR) regulates various liver functions ranging from drug metabolism and excretion to energy metabolism. CAR can also be a risk factor for developing liver diseases such as hepatocellular carcinoma. Here we have characterized the conserved threonine 38 of human CAR as the primary residue that regulates nuclear translocation and activation of CAR. Protein kinase C phosphorylates threonine 38 located on the ␣-helix spanning from residues 29 -42 that constitutes a part of the first zinc finger and continues into the region between the zinc fingers. Molecular dynamics study has revealed that this phosphorylation may destabilize this helix, thereby inactivating CAR binding to DNA as well as sequestering it in the cytoplasm. We have found, in fact, that helix-stabilizing mutations reversed the effects of phosphorylation. Immunohistochemical study using an anti-phosphothreonine 38 peptide antibody has, in fact, demonstrated that the classic CAR activator phenobarbital dephosphorylates the corresponding threonine 48 of mouse CAR in the cytoplasm of mouse liver and translocates CAR into the nucleus. These results define CAR as a cell signal-regulated constitutive active nuclear receptor. These results also provide phosphorylation/dephosphorylation of the threonine as the primary drug target for CAR activation.

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“…Прогресс в понимании молекулярных механизмов индукции ферментов метаболизма ксенобиотиков был сделан после открытия двух рецепторов -прегнан Х-рецептора (PXR) и конститутивного андростанового рецептора (CAR). Как было установлено в многочисленных исследованиях, именно через эти рецепторы в большинстве случаев реализуется ответ организма на поступление ксенобиотиков [14]. В тоже время, CAR и PXR имеют общие лиганды и с другими факторами транскрипции, в частности, с печёночным Х-рецептором (LXR) и рецептором активатора пролиферации пероксисом альфа (PPAR a), а гены CYP2B, CYP2C, CYP3A и CYP2H1 помимо CAR и PXR имеют энхансеры как для рецептора витамина D (VDR), так и для рецепторов тиреоидных гормонов и LXR [15].…”

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Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy

et al. 2015

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We have studied the effect of berberine on the recovery processes of liver xenobiotic-metabolizing function during its compensatory growth after 70% partial hepatectomy. It was found the hepatic ability to metabolize foreign substances are not restored up to day 8. Administration of berberine (10 mg/kg intraperitoneally) for 6 days led to normalization of both cytochrome P450-dependent and flavin-containing monooxygenases. It is suggested that in the biotransformation of berberine involved not only cytochrome P450, but also flavin-containing monooxygenases.

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Induction of Drug Metabolism: The Role of Nuclear Receptors

Cited by 409 publications

References 274 publications

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Changes in the Expression of Cytochromes P450 and Nuclear Receptors in the Liver of Genetically Diabetic db/db Mice

Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3)

Effects of berberine on the recovery of rat liver xenobiotic-metabolizing enzymes after partial hepatectomy

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