Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

Hakkola, Jukka; Bernasconi, Camilla; Coecke, Sandra; Richert, Lysiane; Andersson, Tommy; Pelkonen, Olavi

doi:10.1111/bcpt.13004

Cited by 52 publications

(30 citation statements)

References 62 publications

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“…However, not all the compounds found to be activators in cell or other in vitro assays are actual in vivo activators because of pharmacokinetic or other factors. It has also become clear that AHR, PXR, and CAR not only control the elimination of xenobiotics, but regulate also many other endogenous functions and signaling pathways and their activation may be involved in many chronic diseases such as metabolic diseases and cancer (Hakkola et al 2018 ).…”

Section: Mechanisms Of Cyp Inductionmentioning

confidence: 99%

“…AHR also regulates several phase 2 drug-metabolizing enzymes. In addition to drug metabolism, AHR plays important role in multiple physiological functions such as immunity, cell growth and differentiation, and prolonged activation may cause toxicity (Hakkola et al 2018 ; Kawajiri and Fujii-Kuriyama 2017 ; Nebert 2017 ; Rothhammer and Quintana 2019 ).…”

Section: Mechanisms Of Cyp Inductionmentioning

confidence: 99%

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Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

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The cytochrome P450 (CYP) enzyme family is the most important enzyme system catalyzing the phase 1 metabolism of pharmaceuticals and other xenobiotics such as herbal remedies and toxic compounds in the environment. The inhibition and induction of CYPs are major mechanisms causing pharmacokinetic drug–drug interactions. This review presents a comprehensive update on the inhibitors and inducers of the specific CYP enzymes in humans. The focus is on the more recent human in vitro and in vivo findings since the publication of our previous review on this topic in 2008. In addition to the general presentation of inhibitory drugs and inducers of human CYP enzymes by drugs, herbal remedies, and toxic compounds, an in-depth view on tyrosine-kinase inhibitors and antiretroviral HIV medications as victims and perpetrators of drug–drug interactions is provided as examples of the current trends in the field. Also, a concise overview of the mechanisms of CYP induction is presented to aid the understanding of the induction phenomena.

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Section: Mechanisms Of Cyp Inductionmentioning

confidence: 99%

Section: Mechanisms Of Cyp Inductionmentioning

confidence: 99%

Inhibition and induction of CYP enzymes in humans: an update

et al. 2020

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“…Cytochromes P450 (CYPs) are key enzymes involved in the initial metabolism of drugs in humans, including 70–80% of all drugs in clinical use ( Anzenbacher and Anzenbacherová, 2001 ). The expression of these enzymes is under the control of specific nuclear receptors ( Hakkola et al, 2018 ), and their regulation is influenced by many factors such as genetic polymorphisms, regulation by cytokines, pathological states, age, etc. ( Zanger and Schwab, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences

et al. 2020

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Sexual differences and the composition/function of the gut microbiome are not considered the most important players in the drug metabolism field; however, from the recent data it is obvious that they may significantly affect the response of the patient to therapy. Here, we evaluated the effect of microbial colonization and sex differences on mRNA expression and the enzymatic activity of hepatic cytochromes P450 (CYPs) in germ-free (GF) mice, lacking the intestinal flora, and control specific-pathogen-free (SPF) mice. We observed a significant increase in the expression of Cyp3a11 in female SPF mice compared to the male group. However, the sex differences were erased in GF mice, and the expression of Cyp3a11 was about the same in both sexes. We have also found higher Cyp2c38 gene expression in female mice compared to male mice in both the SPF and GF groups. Moreover, these changes were confirmed at the level of enzymatic activity, where the female mice exhibit higher levels of functional CYP2C than males in both groups. Interestingly, we observed the same trend as with CYP3A enzymes: a diminished difference between the sexes in GF mice. The presented data indicate that the mouse gut microbiome plays an important role in sustaining sexual dimorphism in terms of hepatic gene expression and metabolism.

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“…In liver and other organs, adaptive and toxic responses to xenobiotics are coordinated by xenobiotic receptors (XRs) 20 . Activation of XRs leads to increased transcription of xenobiotic metabolizing enzymes, such as cytochromes P450 (CYP).…”

Section: Gd-liposomes Do Not Change Expression Of Stress-related Genesmentioning

confidence: 99%

Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages

Šimečková

Hubatka

Kotouček

et al. 2020

Sci Rep

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Gadolinium (Gd)-based contrast agents are extensively used for magnetic resonance imaging (MRi). Liposomes are potential nanocarrier-based biocompatible platforms for development of new generations of MRi diagnostics. Liposomes with Gd-complexes (Gd-lip) co-encapsulated with thrombolytic agents can serve both for imaging and treatment of various pathological states including stroke. in this study, we evaluated nanosafety of Gd-lip containing pe-DtpA chelating Gd +3 prepared by lipid film hydration method. We detected no cytotoxicity of Gd-lip in human liver cells including cancer HepG2, progenitor (non-differentiated) HepaRG, and differentiated HepaRG cells. Furthermore, no potential side effects of Gd-lip were found using a complex system including general biomarkers of toxicity, such as induction of early response genes, oxidative, heat shock and endoplasmic reticulum stress, DnA damage responses, induction of xenobiotic metabolizing enzymes, and changes in sphingolipid metabolism in differentiated HepaRG. Moreover, Gd-lip did not show pro-inflammatory effects, as assessed in an assay based on activation of inflammasome NLRP3 in a model of human macrophages, and release of eicosanoids from HepaRG cells. in conclusion, this in vitro study indicates potential in vivo safety of Gd-lip with respect to hepatotoxicity and immunopathology caused by inflammation.Gadolinium (Gd) -based contrast agents are extensively used for magnetic resonance imaging (MRI). Gd +3 forms insoluble phosphate salt in biological fluids and cultivation media. Therefore, Gd +3 is used in complexed forms of soluble chelates. These complexes are believed to be stable and non-toxic because of a high stability constant 1 . Recently, accumulation of Gd-based contrast agents has been demonstrated in various organs like kidney, liver and nervous system. It is supposed that toxic effects can be caused by dissociation of Gd ions from chelated complexes 2,3 . Case reports pointed to the induction of nephrotoxicity, hepatotoxicity and neurotoxicity and rare acute adverse reactions to Gd-based contrast agents were also observed in patients 4 .Liposomes, phospholipid-based vesicles, are widely studied as potential nanocarriers of both MRI contrast agents, including Gd +3 , and drug molecules, such as thrombolytic agents 1,5 . Therefore, liposomes can serve as diagnostic as well as theranostic agents for imaging and treatment of various pathological states and illnesses such as cancer, ischemic stroke and vasculature of different organs including liver and spleen 6,7 . Thus, liposomes represent a favourable platform for a new generation of targeted diagnostic and theranostic systems 8 .Liposomes composed of a Gd-chelating lipid, such as 1,2-distearoyl-sn-glycero-3-p hosphoethanolamine-N-diethylenetriaminepentaacetic acid (PE-DTPA (Gd)), can be easily modified to capture targeting moieties on their surface using different chemistries including copper-free click-chemistry. Moreover, different surface coating of liposomes including polyethylene glycol, hyalu...

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Cytochrome P450 Induction and Xeno‐Sensing Receptors Pregnane X Receptor, Constitutive Androstane Receptor, Aryl Hydrocarbon Receptor and Peroxisome Proliferator‐Activated Receptor α at the Crossroads of Toxicokinetics and Toxicodynamics

Cited by 52 publications

References 62 publications

Inhibition and induction of CYP enzymes in humans: an update

Inhibition and induction of CYP enzymes in humans: an update

Gut Microbiome Alters the Activity of Liver Cytochromes P450 in Mice With Sex-Dependent Differences

Gadolinium labelled nanoliposomes as the platform for MRI theranostics: in vitro safety study in liver cells and macrophages

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