Induction of Rat UDP-Glucuronosyltransferases in Liver and Duodenum by Microsomal Enzyme Inducers That Activate Various Transcriptional Pathways

Shelby, Melinda K.; Klaassen, Curtis D.

doi:10.1124/dmd.106.010397

Cited by 90 publications

(69 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, two other AhR ligands, 3MC and bNF, did not induce 7HC conjugation via UGT1A6 (Ikushiro et al, 2004) or UGT1A7/8 (Webb et al, 2005), which is in line with reported findings that UGT1A6 -8 mRNA expression was not induced in rat duodenum after in vivo administration of bNF (Shelby and Klaassen, 2006). Dexamethasone, a known rodent PXR agonist at the concentration used, induces CYP3A in rat (Savas et al, 1999).…”

Section: Discussionsupporting

confidence: 80%

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

et al. 2007

View full text Add to dashboard Cite

ABSTRACT:The aim of this study was to evaluate drug metabolism in rat small intestinal and colon precision-cut slices during 24 h of incubation and the applicability of these slices for enzyme induction studies. Various parameters were evaluated: intracellular levels of ATP (general viability marker), alkaline phosphatase activity (specific epithelial marker), villin expression (specific epithelial marker), and metabolic rates of 7-ethoxycoumarin (CYP1A), testosterone (CYP3A and CYP2B), and 7-hydroxycoumarin (glucuronide and sulfate conjugation) conversions. ATP and villin remained constant up to, respectively, 5 and 8 h in small intestine and up to 24 h in colon. The metabolic rate remained constant in small intestinal slices up to 8 h and decreased afterward to 24 to 92%, depending on the substrate studied. The inducibility of metabolism in small intestinal and colon slices was tested with several inducers at various concentrations and incubation times. The following inducers were used: 3-methylcholanthrene, ␤-naphthoflavone, indirubin, and tertbutylhydroquinone (aryl hydrocarbon receptor ligands), dexamethasone (glucocorticoid receptor/pregnane X receptor ligand) and phenobarbital (constitutive androstane receptor ligand). After incubation with inducers, metabolic rates were evaluated with 7-ethoxycoumarin and testosterone (phase I) and 7-hydroxycoumarin (phase II) as substrate. All inducers elevated the metabolic rates consistent with the available published in vivo induction data. Induction of enzyme activity was already detectable after 5 h (small intestine) and after 8 h (colon) for 3-methylcholanthrene and ␤-naphthoflavone and was clearly detectable for all tested inducers after 24 h (up to 20-fold compared with noninduced controls). In conclusion, small intestinal and colon precision-cut slices are useful for metabolism and enzyme induction studies.

show abstract

Section: Discussionsupporting

confidence: 80%

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

et al. 2007

View full text Add to dashboard Cite

show abstract

“…In addition to regulation by exogenous inducers, studies with LATF-and Nrf2-deficient mice suggest that basal expression of UGTs is also controlled by the discussed LATFs (indicated by +). Rat UGT induction data are taken from [17], human estimates are described in the text. + indicates < 2-fold, ++ 2- Table Page 28 of 31 A c c e p t e d M a n u s c r i p t …”

Section: Page 13 Of 31mentioning

confidence: 99%

“…In addition, treatment of rats with fibrates led to their characterization as peroxisome proliferators [12], CYP4 family inducers [5], and identification of PPARα as the responsible LATF [13]. It was soon recognized that these inducers also differentially activated other xenobiotic-metabolizing enzymes (XMEs), for example, UGT supergene family members [14] which similar to CYPs are differentially induced in rat liver by aryl hydrocarbons, phenobarbital and fibrates [15][16][17]. Recognition of common LATF-binding response elements in the regulatory region of target genes suggests that Phase I and II XMEs, drug transporters (Phase III) as well as LATFs represent an evolutionary conserved detoxification system for lipid-soluble endo-and xenobiotics [5,11,18,19].…”

Section: Introductionmentioning

confidence: 99%

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Bock¹

2011

Biochemical Pharmacology

View full text Add to dashboard Cite

. From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans. Biochemical Pharmacology, Elsevier, 2011, 82 (1) This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

show abstract

“…29) The present study focused on nuclear receptors, which have been reported to regulate the expression of UGT2B in the liver. UGT2B expression in the liver is regulated primarily by the constitutive androstane receptor (CAR), [30][31][32] a nuclear receptor and conjugating enzyme most highly expressed in the liver; this receptor is also found in the small intestine. In addition to conjugating enzymes such as UGT2B, metabolizing enzymes such as CYP2B [33][34][35] and transporters such as multidrug resistance-associated protein 2 (MRP2) 36,37) are known to be target genes of CAR.…”

mentioning

confidence: 99%

Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain

Kaneta

Ochiai

Nagae

et al. 2016

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Approximately 30% of patients with cancer pain experience concurrent neuropathic pain. Since these patients are not sufficiently responsive to morphine, the development of an effective method of pain relief is urgently needed. Decreased function of the μ opioid receptor, which binds to the active metabolite of morphine M-6-G in the brain, has been proposed as a mechanism for morphine resistance. Previously, we pharmacokinetically examined morphine resistance in mice with neuropathic pain, and demonstrated that the brain morphine concentration was decreased, expression level of P-glycoprotein (P-gp) in the small intestine was increased, and expression level and activity of uridine diphosphate glucuronosyltransferase (UGT)2B in the liver were increased. In order to clarify the mechanism of the increased expression of UGT2B, we examined the phase of neuropathic pain during which UGT2B expression in the liver begins to increase, and whether this increased expression is nuclear receptor-mediated. The results of this study revealed that the increased expression of UGT2B in the liver occurred during the maintenance phase of neuropathic pain, suggesting that it may be caused by transcriptional regulation which was not accompanied by increased nuclear import of pregnane X receptor (PXR). Key words morphine; neuropathic pain; nuclear receptorIt has been reported that the onset of neuropathic pain is closely associated with the immune response around the damaged nerve. When a nerve is injured, histamine, inflammatory cytokines, and chemokines are released from mast cells located in the damaged nerve, inducing the activation and accumulation of neutrophils and macrophages to the nerve site. Subsequently, inflammatory cytokines and chemokines released from the accumulated cells sensitize the primary sensory nerves, 1,2) increasing the release of pain transmitters from the primary sensory nerve endings, resulting in an unusual enhancement of the effect of the pain transmitters on secondary sensory nerves. 3,4) The effect of pain transmitters on secondary sensory nerves is further augmented by the activation of microglia, 5-9) a type of glia cell, in the spinal cord. This accelerates the release of inflammatory cytokines and other factors. It has also been reported that expression of the ligand-gated ion channel pregnane 2 recepter (P2X) receptor is increased in activated microglia. 8,[10][11][12] This induces the release of brain-derived neurotrophic factor (BDNF) from microglia, which binds to the tyrosine kinase receptor B (TrkB) receptor on secondary sensory nerves, downregulating the expression of K-Cl cotransporter 2 (KCC2). 13,14) The reduced expression of KCC2 disinhibits GABAergic neurons, which suppress the sensation of pain under normal conditions, resulting in pain enhancement.15) The expression of P2X receptor and brain-derived neurotrophic factor is also increased by interferon regulatory factor 8 (IRF8), a transcription factor belonging to the interferon regulatory factor family. 16)A recent report states that t...

show abstract

Induction of Rat UDP-Glucuronosyltransferases in Liver and Duodenum by Microsomal Enzyme Inducers That Activate Various Transcriptional Pathways

Cited by 90 publications

References 42 publications

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

Induction of Phase I and II Drug Metabolism in Rat Small Intestine and Colon in Vitro

From differential induction of UDP-glucuronosyltransferases in rat liver to characterization of responsible ligand-activated transcription factors, and their multilevel crosstalk in humans

Mechanism for Increased Expression of UGT2B in the Liver of Mice with Neuropathic Pain

Contact Info

Product

Resources

About