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

Bock, Karl Walter

doi:10.1016/j.bcp.2011.03.011

Cited by 14 publications

(7 citation statements)

References 92 publications

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“…In agreement with our findings, previous studies have also shown that As(III) decreases dexamethasone-mediated induction of CYP3A23 mRNA, protein, and catalytic activity in primary rat hepatocytes (Jacobs et al, 1999). However, these studies used dexamethasone, which primarily induces the glucocorticoid receptor, rather than PXR (Bock, 2011).…”

Section: Inhibition Of Cytochrome P450s By As(iii)supporting

confidence: 92%

Inhibition of Heme Oxygenase-1 Partially Reverses the Arsenite-Mediated Decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 Catalytic Activity in Isolated Rat Hepatocytes

Anwar-Mohamed¹,

Klotz²,

El‐Kadi³

2011

Drug Metab Dispos

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ABSTRACT:Heme oxygenase (HO-1), the rate-limiting enzyme in the physiological breakdown of heme, is ubiquitous, and its expression can be increased by arsenite [As(III)], and similar other stimuli that induce cellular oxidative stress. Interestingly, it has been shown that the As(III)-induced HO-1 is inversely correlated with a decrease in cytochromes P450 (P450s) activity; however, the direct role for HO-1 in the inhibition of P450 enzymes remains unknown. Our results showed that As(III) at a concentration of 5 M decreased the constitutive and inducible expression of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 at the mRNA, protein, and catalytic activity levels. Moreover, As(III) decreased the nuclear accumulation of aryl hydrocarbon receptor (AhR) and pregnane X receptor without increasing their degradation. As(III) also increased the binding of cytosolic AhR to heat shock protein 90 and hepatitis B virus X-associated protein 2. In the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin as an inducer for CYP1A and rifampin as an inducer for CYP3A, As(III) decreased the enzymatic activity of the four P450s more than it decreased their mRNA or protein expression levels. It is noteworthy that treatment with the competitive HO-1 inhibitor, tin-mesoporphyrin, or supplementing external heme partially reversed the As(III)-mediated decrease in activities of the four P450s. In conclusion, the current study provides the first evidence that As(III) decreases CYP1A1, CYP1A2, CYP3A23, and CYP3A2 expression in freshly isolated rat primary hepatocytes. Furthermore, inhibiting the As(III)-mediated induction of HO-1 partially restores the enzymatic activity of these P450s that was initially decreased by As(III), confirming the direct role of HO-1 in the inhibition of P450s.

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Section: Inhibition Of Cytochrome P450s By As(iii)supporting

confidence: 92%

Inhibition of Heme Oxygenase-1 Partially Reverses the Arsenite-Mediated Decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 Catalytic Activity in Isolated Rat Hepatocytes

Anwar-Mohamed¹,

Klotz²,

El‐Kadi³

2011

Drug Metab Dispos

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“…A number of nuclear receptors, including PXR, constitute androstane receptor (CAR), peroxisome proliferator-activated receptor α , retinoid X receptor, and AhR, and transcriptional factors, including nuclear factor-erythroid 2-related factor 2 (Nrf2) and activating protein 1 (AP-1), have been shown to play an important role in the transcription of genes encoding drug-metabolizing enzymes and transporters [39]. For instance, activation of Nrf2, AhR, PXR, and CAR upregulates the transcription of UGT and GST in a coordinated manner [40, 41]. AhR is the key mediator of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced changes in CYP1A genes [42].…”

Section: Discussionmentioning

confidence: 99%

Andrographis paniculataExtract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats

Chen

Huang

Liu

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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Andrographolide is the most abundant terpenoid of A. paniculata which is used in the treatment of diabetes. In this study, we investigated the effects of A. paniculata extract (APE) and andrographolide on the expression of drug-metabolizing enzymes in rat liver and determined whether modulation of these enzymes changed the pharmacokinetics of tolbutamide. Rats were intragastrically dosed with 2 g/kg/day APE or 50 mg/kg/day andrographolide for 5 days before a dose of 20 mg/kg tolbutamide was given. APE and andrographolide reduced the AUC0–12 h of tolbutamide by 37% and 18%, respectively, compared with that in controls. The protein and mRNA levels and enzyme activities of CYP2C6/11, CYP1A1/2, and CYP3A1/2 were increased by APE and andrographolide. To evaluate whether APE or andrographolide affected the hypoglycemic action of tolbutamide, high-fat diet-induced obese mice were used and treated in the same manner as the rats. APE and andrographolide increased CYP2C6/11 expression and decreased plasma tolbutamide levels. In a glucose tolerance test, however, the hypoglycemic effect of tolbutamide was not changed by APE or andrographolide. These results suggest that APE and andrographolide accelerate the metabolism rate of tolbutamide through increased expression and activity of drug-metabolizing enzymes. APE and andrographolide, however, do not impair the hypoglycemic effect of tolbutamide.

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“…GSTs are required for detoxification of electrophilic compounds by reaction with glutathione [50]. UGTs also contribute to the antioxidant response by catalyzing conjugation of glucuronic acid, for instance, with quinols, thereby facilitating their excretion [51]. Interestingly, some ligands are able to differentially activate the AhR/Nrf2/NQO1 pathway while the AhR/CYP1A1 axis is only weakly induced.…”

Section: The Ahr-nrf2 Pathwaymentioning

confidence: 99%

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Dietrich

2016

Stem Cells International

121

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The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT) and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

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

Cited by 14 publications

References 92 publications

Inhibition of Heme Oxygenase-1 Partially Reverses the Arsenite-Mediated Decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 Catalytic Activity in Isolated Rat Hepatocytes

Inhibition of Heme Oxygenase-1 Partially Reverses the Arsenite-Mediated Decrease of CYP1A1, CYP1A2, CYP3A23, and CYP3A2 Catalytic Activity in Isolated Rat Hepatocytes

Andrographis paniculataExtract and Andrographolide Modulate the Hepatic Drug Metabolism System and Plasma Tolbutamide Concentrations in Rats

Antioxidant Functions of the Aryl Hydrocarbon Receptor

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