Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Lee, Sang Yoon; Lee, Ji-Yoon; Kim, Youngmi; Kim, Sang Kyum; Oh, Soo Jin

doi:10.1016/j.toxlet.2015.03.015

Cited by 16 publications

(7 citation statements)

References 36 publications

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“…The role of CYP enzymes in general appeared to be minor in nature. As expected, pharmacokinetic interaction with rifampicin showed a modest effect on the decreased exposure or increased clearance of cediranib, which was consistent with the induction of UGT1A4 by rifampicin [ 10 – 12 ] (Table 1 ).…”

Section: Drug–drug Interactions (Ddis) With Oral Anticancer Drugssupporting

confidence: 78%

Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms

Srinivas¹

2016

Drugs R D

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Since many drugs are cytochrome P450 (CYP)-3A4 substrates, it has become common practice to assess drug–drug interaction (DDI) potential with a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) in early drug development. Such an evaluation is relevant to anticancer drugs with metabolism governed by CYP3A4. DDIs with rifampicin are complex, involving other physiological mechanisms that may impact overall pharmacokinetics. Our objective was to study and delineate such mechanisms for oral versus intravenous anticancer drugs. We hypothesized that DDIs between anticancer drugs and rifampicin were primarily driven by CYP3A4 induction. This hypothesis was proven for the oral anticancer drugs; however, in some cases, other intrinsic mechanisms such as P-glycoprotein (Pgp)/UDP glucuronosyl transferase (UGT) induction and transporter inhibition may have played an important role alongside the induced CYP3A4 enzymes. The hypothesis that CYP3A4 induction would decrease drug exposure appeared paradoxical for intravenous romidepsin and—to a somewhat lesser extent—for cabazitaxel. In light of this dilemma in the interpretation of the pharmacokinetic data with rifampicin, several questions require further consideration. Given the complexity and paradoxical effects arising with DDIs with rifampicin, the continued preference for rifampicin as CYP3A4 inducer needs immediate re-appraisal.

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Section: Drug–drug Interactions (Ddis) With Oral Anticancer Drugssupporting

confidence: 78%

Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms

Srinivas¹

2016

Drugs R D

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“…In the liver, BA hydroxylation and hydrophobicity are regulated by phase I enzymes like Cyp2b10 as well as Cyp3a11, and phase II enzymes like Ugt1a1 and Sult2a1 (Meng et al, 2015b). Cyp3a11 is a target gene of pregnane X receptor (PXR), and Cyp2b10 is a target gene of constitutive androstane receptor (CAR) (Lee et al, 2015) Supplementary Figure S2. Sult2a1 is the target gene of FXR (Meng et al, 2015b).…”

Section: Discussionmentioning

confidence: 99%

SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model

Liu

Yuan

et al. 2017

Front. Pharmacol.

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Intrahepatic cholestasis is a kind of clinical syndrome along with hepatotoxicity which caused by intrahepatic and systemic accumulations of bile acid. There are several crucial generating factors of the pathogenesis of cholestasis, such as inflammation, dysregulation of bile acid transporters and oxidative stress. SIRT1 is regarded as a class III histone deacetylase (HDAC). According to a set of researches, SIRT1 is one of the most important factors which can regulate the hepatic bile acid metabolism. SRT1720 is a kind of activator of SIRT1 which is 1000 times more potent than resveratrol, and this paper is aimed to study its protective influence on hepatotoxicity and cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in mice. The findings revealed that SRT1720 treatment increased FXR and Nrf2 gene expressions to shield against hepatotoxicity and cholestasis induced by ANIT. The mRNA levels of hepatic bile acid transporters were also altered by SRT1720. Furthermore, SRT1720 enhanced the antioxidative system by increasing Nrf2, SOD, GCLc, GCLm, Nqo1, and HO-1 gene expressions. In conclusion, a protective influence could be provided by SRT1720 to cure ANIT-induced hepatotoxicity and cholestasis, which was partly through FXR and Nrf2 activations. These results indicated that SIRT1 could be regarded as a therapeutic target to cure the cholestasis.

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“…Regarding drug metabolism pathways, similar to the mouse receptors, in HepG2 cells hPXR and hCAR activated by herbal supplements also up-regulate the expression and activities of CYP2B6, which is the human homolog of mouse Cyp2b10 (Xu et al, 2015). Regarding hPXR signaling, the hPXR ligand rifampicin treated hPXR/hCAR-double-humanized mice had increased hepatic microsomal protein, total Cyp contents, Cyp reductase activity, and UGT activity (Lee et al, 2015). Regarding hCAR signaling, genes encoding drug-metabolizing enzymes are among the main clusters altered by both the hCAR ligand CITCO, and the species-unspecific CAR activator phenobarbital (which can also activate PXR) (Li et al, 2015), whereas similar results were observed in livers of mice treated with TCPOBOP (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome

Cui

Klaassen

2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

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The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200 mg/kg, i.p. once daily for 4 days in corn oil) or the prototypical CAR ligand TCPOBOP (3 mg/kg, i.p., once daily for 4 days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated drug-processing genes (DPGs), phase-I and –II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the entire hepatic transcriptome correlated with a marked change in the expression of many DNA and histone epigenetic modifiers. In conclusion, the present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands. Results from this study will further support the role of these receptors in regulating the homeostasis of xenobiotic and intermediary metabolism in liver, and aid in distinguishing between PXR and CAR signaling at various physiological and pathophysiological conditions.

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Expression of hepatic cytochrome P450s and UDP-glucuronosyltransferases in PXR and CAR double humanized mice treated with rifampicin

Cited by 16 publications

References 36 publications

Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms

Pharmacokinetic Interaction of Rifampicin with Oral Versus Intravenous Anticancer Drugs: Challenges, Dilemmas and Paradoxical Effects Due to Multiple Mechanisms

SRT1720 Alleviates ANIT-Induced Cholestasis in a Mouse Model

RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome

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