The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes

Howe, Katharine; Sanat, Faizah; Thumser, Alfred E.; Coleman, Tanya; Plant, Nick

doi:10.3109/00498254.2011.569773

Cited by 56 publications

(40 citation statements)

References 33 publications

(31 reference statements)

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“…Our current results indicated that hepatic FXR was stimulated by SV in the context of HFD feeding, and this effect was impaired by antibiotic treatment. It is reported that the activation of FXR by statins is associated with their diversified actions 42 , however, little is known about the relationship between the hypolipidemic effect of statins and activation of hepatic FXR so far. Our current results revealed that the hypolipidemic effect of SV might be associated with the stimulation of hepatic FXR and FXR-regulated targeted genes, which could be impaired by gut microbiota modulation.…”

Section: Discussionmentioning

confidence: 99%

Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice

Zheng

et al. 2017

J. Proteome Res.

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Interindividual differences in hypolipidemic effect of simvastatin are observed in clinic, and metabolomic studies have uncovered the association between variations of bacterial-derived metabolites and therapeutic outcomes. In current study, we investigated the gut microbial-involved mechanisms underlying the different responses to simvastatin. Male C57BL/6J mice were given high-fat/cholesterol diet (HFD) 8 weeks and then orally administered simvastatin (20 mg/kg, once a day) for 4 weeks with or without antibiotic (100 mg/kg Imipenem : Cilastatin Sodium). We observed simvastatin reduced the levels of serum TC, LDL, HDL and TG in HFD-fed mice, but this effect was attenuated by antibiotic which altered gut microbiota composition. Subsequent metabolomic study indicated that gut microbiota modulation changed the serum metabolic and bile acid profiles in simvastatin-treated mice. Moreover, our results showed that simvastatin stimulated the expression of hepatic CYP7A1, CYP7B1 and Farnesoid X receptor (FXR) in HFD-fed mice, which were impaired by gut microbiota modulation. In summary, our results revealed that the hypolipidemic effect of simvastatin was correlated with the composition of gut microbiota, and the attenuated hypolipidemic effect of simvastatin by gut microbiota modulation was associated with the suppression on hepatic CYP7A1, CYP7B1 and FXR proteins that regulate bile acids synthesis from cholesterol.

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Section: Discussionmentioning

confidence: 99%

Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice

Zheng

et al. 2017

J. Proteome Res.

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“…Nuclear reporter activation assays were undertaken using a modification of the Checkmate mammalian two-hybrid system (Promega, UK), as described previously (Howe et al, 2011). Briefly, Huh7 cells were seeded into 96-well plates (Nunc International, Leicestershire, UK) at a concentration of 20,000 cells/well and incubated at 37 C for 24 hrs.…”

Section: Methodsmentioning

confidence: 99%

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

Al-Salman

Plant

2012

Toxicology and Applied Pharmacology

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“…atorvastatin, lovastatin and simvastatin) are majorly metabolized by CYP3A4. Other statin drugs including atorvastatin, simvastatin, rosuvastatin, lovastatin and pravastatin can induce CYP2B6 and CYP2C9 in addition to CYP3A4 via activation of the pregnane X receptor (PXR) [133, 134]. Two clinical studies reported that continuous treatment of 80 mg atorvastatin significantly enhanced clopidogrel bioactivation and efficacy in both healthy volunteers and PCI patients with or without diabetes mellitus [135, 136].…”

Section: Covariates That Affect Clopidogrel Dose/pk/pdmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

et al. 2015

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Acute coronary syndromes (ACS) remain life-threatening disorders that are associated with high morbidity and mortality. Dual-antiplatelet therapy with aspirin and clopidogrel has shown to reduce cardiovascular events in patients with ACS. However, there is substantial inter-individual variability in response to clopidogrel treatment in addition to prolonged recovery of platelet reactivity as a result of irreversible binding to P2Y12 receptors. This high inter-individual variability in treatment response has primarily been associated with genetic polymorphisms in the genes encoding for cytochrome (CYP) 2C19 that affect clopidogrel’s pharmacokinetics. While FDA has issued a boxed warning for CYP2C19 poor metabolizers due to a potentially reduced efficacy in these patients, results from multivariate analyses suggest that additional factors, including age, sex, obesity, concurrent diseases and drug-drug interactions, may all contribute to the overall between-subject variability in treatment response. However, the extent to which each of these factors contributes to the overall variability and how they are interrelated is currently unclear. The objective of this review article is to provide a comprehensive update on the different factors that influence clopidogrel’s pharmacokinetics and pharmacodynamics and how they mechanistically contribute to inter-individual differences in response to clopidogrel treatment.

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The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes

Abstract: This demonstration of their ability to directly activate nuclear receptors, leading to nuclear receptor cross-talk, has important potential implications for their use within a polypharmacy paradigm.

Cited by 56 publications

References 33 publications

Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice

Gut Microbiota Modulation Attenuated the Hypolipidemic Effect of Simvastatin in High-Fat/Cholesterol-Diet Fed Mice

Non-coplanar polychlorinated biphenyls (PCBs) are direct agonists for the human pregnane-X receptor and constitutive androstane receptor, and activate target gene expression in a tissue-specific manner

Clinical Pharmacokinetics and Pharmacodynamics of Clopidogrel

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