Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism

Smutný, Tomás̆; Hyršová, Lucie; Braeuning, Albert; Ingelman‐Sundberg, Magnus; Pávek, Petr

doi:10.1007/s00204-020-02916-x

Cited by 12 publications

(10 citation statements)

References 97 publications

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“…Despite the complex regulatory mechanisms of nuclear receptor, some of them are significant and to be covered. Taking miRNAs as example: miRNAs modify the function of PXR through regulating corresponding transporters and enzymes, combined with the 3′-UTR of PXR mRNA and targeting other transcription factors, nuclear receptors as well as its dimer partners like RXR (Smutny et al, 2021). Also, the co-drug strategy is also to be studied.…”

Section: Discussionmentioning

confidence: 99%

Patchouli Alcohol Modulates the Pregnancy X Receptor/Toll-like Receptor 4/Nuclear Factor Kappa B Axis to Suppress Osteoclastogenesis

et al. 2021

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The incidence of osteoporosis, which is primarily characterized by plethoric osteoclast (OC) formation and severe bone loss, has increased in recent years. Millions of people worldwide, especially postmenopausal women, suffer from osteoporosis. The drugs commonly used to treat osteoporosis still exist many disadvantages, but natural extracts provide options for the treatment of osteoporosis. Therefore, the identification of cost-effective natural compounds is important. Patchouli alcohol (PA), a natural compound extracted from Pogostemon cablin that exerts anti-inflammatory effects, is used as a treatment for gastroenteritis. However, no research on the use of Patchouli alcohol in osteoporosis has been reported. We found that PA dose-dependently inhibited the receptor activator of nuclear factor kappa-B ligand (RANKL)-induced formation and function of OCs without cytotoxicity. Furthermore, these inhibitory effects were reflected in the significant effect of PA on the NF-κB signaling pathway, as PA suppressed the transcription factors NFATc1 and c-Fos. We also determined that PA activated expression of the nuclear receptor pregnane X receptor (PXR) and promoted the PXR/Toll-like receptor 4 (TLR4) axis to inhibit the nuclear import of NF-κB (p50 and p65). Additionally, PA exerted therapeutic effects against osteoporosis in ovariectomized (OVX) mice, supporting the use of PA as a treatment for osteoporosis in the future.

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Section: Discussionmentioning

confidence: 99%

Patchouli Alcohol Modulates the Pregnancy X Receptor/Toll-like Receptor 4/Nuclear Factor Kappa B Axis to Suppress Osteoclastogenesis

et al. 2021

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“…PPARα activates PXR expression by binding to the region −1514 to −1321 bp. Moreover, forced overexpression of ERα or GRα exerts a positive effect on the activity of a PXR reporter construct carrying a 2.2 kbp proximal promoter sequence [ 115 , 116 , 117 ].…”

Section: Mechanisms Of Cyp3a Regulationmentioning

confidence: 99%

The Role of CYP3A in Health and Disease

2022

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CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes’ activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.

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“…However, PXR phosphorylation, acetylation, and ubiquitination inhibit PXR activity by regulating its subcellular localization, co-regulatory interaction, and degradation (Biswas et al, 2011, Cui et al, 2020, Hu et al, 2020, Rana et al, 2013. There is mounting evidence that non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), modulate the function and expression of PXR posttranscriptionally (Smutny et al, 2021).…”

Section: Pxr and Its Ligandsmentioning

confidence: 99%

The Function of Xenobiotic Receptors in Metabolic Diseases

Zhang

Jia

et al. 2022

Drug Metab Dispos

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Metabolic diseases are a series of metabolic disorders that include obesity, diabetes, insulin resistance, hypertension, and hyperlipidemia. The increased prevalence of metabolic diseases has resulted in higher mortality and mobility rates over the past decades, and this has led to extensive research focusing on the underlying mechanisms. Xenobiotic receptors (XRs) are a series of xenobioticsensing nuclear receptors that regulate their downstream target genes expression, thus defending the body from xenobiotic and endotoxin attacks. XR activation is associated with the development of a number of metabolic diseases such as obesity, nonalcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular diseases, thus suggesting an important role for XRs in modulating metabolic diseases.However, the regulatory mechanism of XRs in the context of metabolic disorders under different nutrient conditions is complex and remains controversial. This review summarizes the effects of XRs on different metabolic components (cholesterol, lipids, glucose, and bile acids) in different tissues during metabolic diseases. As chronic inflammation plays a critical role in the initiation and progression of metabolic diseases, we also discuss the impact of XRs on inflammation to comprehensively recognize the role of XRs in metabolic diseases. This will provide new ideas for treating metabolic diseases by targeting XRs.

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Transcriptional and post-transcriptional regulation of the pregnane X receptor: a rationale for interindividual variability in drug metabolism

Cited by 12 publications

References 97 publications

Patchouli Alcohol Modulates the Pregnancy X Receptor/Toll-like Receptor 4/Nuclear Factor Kappa B Axis to Suppress Osteoclastogenesis

Patchouli Alcohol Modulates the Pregnancy X Receptor/Toll-like Receptor 4/Nuclear Factor Kappa B Axis to Suppress Osteoclastogenesis

The Role of CYP3A in Health and Disease

The Function of Xenobiotic Receptors in Metabolic Diseases

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