Downregulation of Mouse Hepatic CYP3A Protein by 3-Methylcholanthrene Does Not Require Cytochrome P450-Dependent Metabolism

Lee, Chunja; Ding, Xinxin; Riddick, David S.

doi:10.1124/dmd.113.052993

Cited by 10 publications

(7 citation statements)

References 26 publications

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“…However, one cannot exclude that SLC16A1 expression could also be modulated by direct interactions between PXR and other cofactors. For instance, it was previously shown that interaction of PXR with AhR could regulate the basal level of CYP3A4 expression and its activation by PXR agonists both in vitro and in vivo [ 51 , 52 , 53 ]. It was also demonstrated that both AhR and PXR could regulate the expression of UGT1A1 by binding to different promotor regions of this PXR target gene [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Matheux

Gassiot

Fromont

et al. 2021

Cancers

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Resistance to castration is a crucial issue in the treatment of metastatic prostate cancer. Kinase inhibitors (KIs) have been tested as potential alternatives, but none of them are approved yet. KIs are subject of extensive metabolism at both the hepatic and the tumor level. Here, we studied the role of PXR (Pregnane X Receptor), a master regulator of metabolism, in the resistance to KIs in a prostate cancer setting. We confirmed that PXR is expressed in prostate tumors and is more frequently detected in advanced forms of the disease. We showed that stable expression of PXR in 22Rv1 prostate cancer cells conferred a resistance to dasatinib and a higher sensitivity to erlotinib, dabrafenib, and afatinib. Higher sensitivity to afatinib was due to a ~ 2-fold increase in its intracellular accumulation and involved the SLC16A1 transporter as its pharmacological inhibition by BAY-8002 suppressed sensitization of 22Rv1 cells to afatinib and was accompanied with reduced intracellular concentration of the drug. We found that PXR could bind to the SLC16A1 promoter and induced its transcription in the presence of PXR agonists. Together, our results suggest that PXR could be a biomarker of response to kinase inhibitors in castration-resistant prostate cancers.

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Section: Discussionmentioning

confidence: 99%

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Matheux

Gassiot

Fromont

et al. 2021

Cancers

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“…Incubations were done in triplicates and repeated once. The same assay kit has previously been used to measure mouse Cyp3a activity (Lee et al, 2013;Selwyn et al, 2015;Li et al, 2017).…”

Section: Downloaded Frommentioning

confidence: 99%

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Han¹,

Wang²,

Shi³

et al. 2020

Drug Metab Dispos

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The microbiome and pregnancy are known to alter drug disposition, yet the interplay of the two physiologic factors on the expression and/or activity of drug metabolizing enzymes and transporters (DMETs) is unknown. This study investigated the effects of microbiome on host hepatic DMETs in mice during pregnancy by comparing four groups of conventional (CV) and germ-free (GF) female mice and pregnancy status, namely, CV nonpregnant, GF non-pregnant, CV pregnant, and GF pregnant mice. Transcriptomic and targeted proteomics of hepatic DMETs were profiled by using multiomics. Plasma bile acid and steroid hormone levels were quantified by liquid chromatography tandem mass spectrometry. CYP3A activities were measured by mouse liver microsome incubations. The trend of pregnancy-induced changes in the expression or activity of hepatic DMETs in CV and GF mice was similar; however, the magnitude of change was noticeably different. For certain DMETs, pregnancy status had paradoxical effects on mRNA and protein expression in both CV and GF mice. For instance, the mRNA levels of Cyp3a11, the murine homolog of human CYP3A4, were decreased by 1.7-fold and 3.3-fold by pregnancy in CV and GF mice, respectively; however, the protein levels of CYP3A11 were increased similarly ∼twofold by pregnancy in both CV and GF mice. Microsome incubations revealed a marked induction of CYP3A activity by pregnancy that was 10-fold greater in CV mice than that in GF mice. This is the first study to show that the microbiome can alter the expression and/or activity of hepatic DMETs in pregnancy. SIGNIFICANCE STATEMENTWe demonstrated for the first time that microbiome and pregnancy can interplay to alter the expression and/or activity of hepatic drug metabolizing enzymes and transporters. Though the trend of pregnancy-induced changes in the expression or activity of hepatic drug metabolizing enzymes and transporters in conventional and germ-free mice was similar, the magnitude of change was noticeably different.

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“…Male and female humanized PXR-CAR-CYP3A4/3A7 mice were exposed to MC under conditions previously shown to downregulate hepatic Cyp3a11 expression and activity in male wild-type C57BL/6 mice (Lee et al, 2006(Lee et al, , 2013a. MC treatment had minimal effects on the liver to body weight ratio, with a 25% increase seen at 72 hours postdosing only in females (Supplemental Fig.…”

Section: Resultsmentioning

confidence: 92%

“…Studies of the regulation of the major CYP3A4 counterpart in mice (Cyp3a11) by 3-methylcholanthrene (MC), a model PAH that is readily biotransformed by P450s (Riddick et al, 1994), have provided valuable insight. Our laboratory showed a pronounced loss of mouse hepatic Cyp3a11 protein triggered by MC treatment (Lee et al, 2006) and subsequently established that the suppression of Cyp3a11 mRNA and protein caused by MC is comparable in wild-type and liver Cpr-null mice that are nearly devoid of hepatic microsomal P450 activity due to hepatocyte-specific conditional deletion of NADPH-cytochrome P450 oxidoreductase (Lee et al, 2013a). Thus, MC appears to downregulate mouse hepatic Cyp3a11 via a pretranslational mechanism that does not require hepatic microsomal P450-dependent activity.…”

Section: Introductionmentioning

confidence: 93%

Suppression of HepaticCYP3A4Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice

Crosby

Riddick

2018

Drug Metab Dispos

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Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, thereby triggering a range of biologic responses, exemplified by the induction of CYP1A1. PAHs can also regulate the expression of members of the CYP3A subfamily, with reports of mainly suppressive effects on mouse hepatic Cyp3a11 expression, but paradoxically both inductive and suppressive effects on human hepatic CYP3A4 expression. Understanding the regulation of CYP3A4 expression by PAHs is important because of the widespread exposure of humans to these chemicals and the central role of the CYP3A4 enzyme in the metabolism of clinically important drugs and endogenous substances. The present study used 3-methylcholanthrene (MC) as a model PAH to characterize the in vivo regulation of CYP3A4 expression and activity in humanized pregnane X receptor-constitutive androstane receptor-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. As a positive control response, pronounced induction of hepatic Cyp1a1 by MC was confirmed at both time points in males and females at the mRNA, protein, and catalytic activity levels. Basal hepatic CYP3A4 expression and activity were significantly higher in female versus male mice. MC treatment suppressed hepatic CYP3A4 in female mice at 72 hours postdosing at the mRNA, protein, and catalytic activity levels. A similar response was observed in male mice, although the suppression of CYP3A4 protein levels did not achieve statistical significance. This mouse model will facilitate further studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.

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Downregulation of Mouse Hepatic CYP3A Protein by 3-Methylcholanthrene Does Not Require Cytochrome P450-Dependent Metabolism

Cited by 10 publications

References 26 publications

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

PXR Modulates the Prostate Cancer Cell Response to Afatinib by Regulating the Expression of the Monocarboxylate Transporter SLC16A1

Impact of Microbiome on Hepatic Metabolizing Enzymes and Transporters in Mice during Pregnancy

Suppression of HepaticCYP3A4Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice

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