Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR

Zhang, Xiaojie; Shi, Zhe; Lyv, Jing-Xi; He, Xuyan; Englert, Neal A.; Zhang, Shuyun

doi:10.1093/toxsci/kfv142

Cited by 36 publications

(39 citation statements)

References 34 publications

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“…Elevated plasma ALT and DBIL levels observed in our study reflected rat liver injury caused by pyrene. Our previous study demonstrated that oral administration of pyrene for 4 days induced hepatotoxicity in adult male mice (C57BL/6 genetic background) at the dose of 300 mg/kg . The 300 mg/kg pyrene dose used in our previous study in mice was approximately 37.5% of the mouse LD 50 , while the 1500 mg/kg dose performed in this study was approximately 54.5% of the rat LD 50 .…”

Section: Discussionmentioning

confidence: 53%

“…Chen et al demonstrated that coke oven emissions primarily consisting of PAHs, including 25% pyrene, significantly induced serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase in coke oven workers . Our previously identified that constitutive androstane receptor (CAR) activation was responsible for pyrene‐induced mouse hepatotoxicity in studies with CAR knockout (CAR KO) mice . However, the toxic effects of pyrene are not completely understood.…”

Section: Introductionmentioning

confidence: 99%

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Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Zhu

Zhao

Wang

et al. 2018

Environmental Toxicology

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Polycyclic aromatic hydrocarbons (PAHs) are a group of persistent organic pollutants primarily formed from the incomplete combustion of carbonaceous materials, and have adverse effects on human health. In this study, we investigated whether pyrene, a PAH consisting of 4 fused benzene rings, has adverse effects on rat. Adult male Sprague‐Dawly rats were treated daily by oral gavage with vehicle (corn oil) or pyrene at doses of 375, 750, 1500, or 2200 mg/kg/day for 4 days. The results showed that pyrene caused hepatotoxicity in rats. When compared with the control group, relative liver weights, plasma alanine aminotransferase, and direct bilirubin levels significantly increased after pyrene exposure. Hepatocyte swelling and degeneration and decreased hepatic total glutathione (GSH) levels were also found in pyrene‐exposed rats. We further observed that mRNA levels of several hepatic metabolizing enzymes regulated by constitutive androstane receptor (CAR) such as CYP2B1 and CYP2B2 significantly increased in pyrene‐exposed rats. These results suggest that decreased GSH levels, elevated hepatic metabolizing enzyme gene expression, and CAR activation are important contributors for pyrene‐induced hepatotoxicity in rats. Additionally, we found pyrene significantly induced plasma inflammatory indices including white blood cell and lymphocyte counts. We also observed that pyrene exposure increased relative weight of kidneys and disrupted kidney function with elevated urea and creatinine levels in rats.

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Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Zhu

Zhao

Wang

et al. 2018

Environmental Toxicology

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“…6C). Likewise, mCAR-independent induction of CYP1A1 and/or CYP1A2 by pyrene and TCPOBOP was observed in both WT and CAR-KO mice [45, 46]. Whereas cell-based CYP1A1 luciferase reporter assays revealed that CITCO does not active AhR (Data not shown).…”

Section: Discussionmentioning

confidence: 97%

Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells

Mackowiak

Brayman³

et al. 2015

Biochemical Pharmacology

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The constitutive androstane receptor (CAR) modulates the transcription of numerous genes involving drug metabolism, energy homeostasis, and cell proliferation. Most functions of CAR however were defined from animal studies. Given the known species difference of CAR and the significant cross-talk between CAR and the pregnane X receptor (PXR), it is extremely difficult to decipher the exact role of human CAR (hCAR) in gene regulation, relying predominantly on pharmacological manipulations. Here, utilizing a newly generated hCAR-knockout (KO) HepaRG cell line, we carried out RNA-seq analysis of the global transcriptomes in wild-type (WT) and hCAR-KO HepaRG cells treated with CITCO, a selective hCAR agonist, phenobarbital (PB), a dual activator of hCAR and hPXR, or vehicle control. Real-time PCR assays in separate experiments were used to validate RNA-seq findings. Our results indicate that genes encoding drug-metabolizing enzymes are among the main clusters altered by both CITCO and PB. Specifically, CITCO significantly changed the expression of 135 genes in an hCAR-dependent manner, while PB altered the expression of 227 genes in WT cells of which 94 were simultaneously modulated in both cell lines reflecting dual effects of PB on hCAR/PXR. Notably, we found that many genes promoting cell proliferation and tumorigenesis were up-regulated in hCAR-KO cells, suggesting that hCAR may play an important role in cell growth that differs from mouse CAR. Together, our results reveal both novel and known targets of hCAR and support the role of hCAR in maintaining the homeostasis of metabolism and cell proliferation in the liver.

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“…The well characterized endogenous ligands of CAR include bilirubin, bile acids, and androstanes [129–132]. Exogenous CAR activators include medications (such as phenobarbital), environmental pollutants (PCBs) and pesticides/pesticide metabolites (methoxychlor, dichlorodiphenyldichloroethylene — DDE), and pyrene [84,133–135]. CAR ligands are species-specific which can be attributed to limited conservation of CAR’s ligand binding domain.…”

Section: Constitutive Androstane Receptormentioning

confidence: 99%

Nuclear receptors and nonalcoholic fatty liver disease

Cave

Clair

Hardesty

et al. 2016

Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanism

233

204

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Nuclear receptors are transcription factors which sense changing environmental or hormonal signals and effect transcriptional changes to regulate core life functions including growth, development, and reproduction. To support this function, following ligand-activation by xenobiotics, members of subfamily 1 nuclear receptors (NR1s) may heterodimerize with the retinoid X receptor (RXR) to regulate transcription of genes involved in energy and xenobiotic metabolism and inflammation. Several of these receptors including the peroxisome proliferator-activated receptors (PPARs), the pregnane and xenobiotic receptor (PXR), the constitutive androstane receptor (CAR), the liver X receptor (LXR) and the farnesoid X receptor (FXR) are key regulators of the gut:liver:adipose axis and serve to coordinate metabolic responses across organ systems between the fed and fasting states. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and may progress to cirrhosis and even hepatocellular carcinoma. NAFLD is associated with inappropriate nuclear receptor function and perturbations along the gut:liver:adipose axis including obesity, increased intestinal permeability with systemic inflammation, abnormal hepatic lipid metabolism, and insulin resistance. Environmental chemicals may compound the problem by directly interacting with nuclear receptors leading to metabolic confusion and the inability to differentiate fed from fasting conditions. This review focuses on the impact of nuclear receptors in the pathogenesis and treatment of NAFLD. Clinical trials including PIVENS and FLINT demonstrate that nuclear receptor targeted therapies may lead to the paradoxical dissociation of steatosis, inflammation, fibrosis, insulin resistance, dyslipidemia and obesity. Novel strategies currently under development (including tissue-specific ligands and dual receptor agonists) may be required to separate the beneficial effects of nuclear receptor activation from unwanted metabolic side effects. The impact of nuclear receptor crosstalk in NAFLD is likely to be profound, but requires further elucidation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.

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Pyrene is a Novel Constitutive Androstane Receptor (CAR) Activator and Causes Hepatotoxicity by CAR

Cited by 36 publications

References 34 publications

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Identification of hepatotoxicity and renal dysfunction of pyrene in adult male rats

Genome-wide analysis of human constitutive androstane receptor (CAR) transcriptome in wild-type and CAR-knockout HepaRG cells

Nuclear receptors and nonalcoholic fatty liver disease

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