Role of Cytochrome P450s in Inflammation

Christmas, Peter

doi:10.1016/bs.apha.2015.03.005

Cited by 50 publications

(36 citation statements)

References 152 publications

(173 reference statements)

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“…Toxic plasma concentrations have been documented in children with influenza B who were also undergoing long‐term therapy with theophylline for asthma (Kraemer et al, ). It is hypothesized that downregulation of P450s enzymes by viral‐induced inflammatory cytokines decreased clearance of theophylline leading to toxic plasma concentrations (Christmas, ). Similar reports of theophylline toxicity exist in cattle with bovine respiratory disease complex (McKenna, Kortiz, Neff‐Davis, Langston, & Berger, ).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a modified, compounded theophylline product in dogs

Cavett

McKiernan

et al. 2019

Vet Pharm & Therapeutics

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Theophylline is a commonly used bronchodilator drug for treatment of chronic canine bronchitis, but no formulations validated in dogs are currently available. An oral, modified and compounded theophylline product (MCT), which could fulfil this need, is available through a USP‐compliant, veterinary compounding pharmacy; however, its pharmacokinetic properties are unknown. The aim of this study was to determine the pharmacokinetics of MCT. Plasma drug concentrations were measured in seven healthy, fed dogs after single doses of intravenous aminophylline (8.6 mg/kg theophylline equivalent) and oral MCT (10 mg/kg). Systemic bioavailability of the MCT was 96.2 ± 32.9%. MCT times to maximum concentration, mean absorption time and terminal half‐life were 8.85 ± 3.63, 6.95 ± 3.42, and 8.67 ± 1.62 hr, respectively. Based on simulations of 10 mg/kg and 12‐hr dosing, steady‐state plasma theophylline concentrations are expected to exceed the minimum therapeutic concentration for 71.7 ± 35.6% of the dosing interval. Overall, the MCT product investigated showed similar pharmacokinetic characteristics compared to previously validated extended‐release theophylline products. An oral dose of 10 mg/kg q 12 hr is likely an appropriate dosage to begin therapy; however, therapeutic drug monitoring may be warranted because of inter‐individual variation.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of a modified, compounded theophylline product in dogs

Cavett

McKiernan

et al. 2019

Vet Pharm & Therapeutics

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“…Table 2). Recent studies have established a regulatory role for cytochrome P450 epoxygenases and hydroxylases in inflammation via the ability to metabolize multiple substrates related to the regulation of inflammation and lipid homeostasis (57). Perhaps, downregulation of cytochromes may exacerbate the hyperactive immunity phenotype, observed in the DM.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging

Odnokoz

Nakatsuka

Klichko

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.

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“…A number of clinical studies have demonstrated suppressed CYP3A4 phenotype during inflammatory conditions (Mayo et al, 2000;Rivory et al, 2002;Molanaei et al, 2012), and several cytokines [interleukin (IL)-1b, IL-1a, IL-6, and tumor necrosis factor (TNF)-a] have been reported to downregulate activity of multiple P450 enzymes in rodent and cell models (Renton, 2005;Aitken and Morgan, 2007). Cytokines, which are formed as part of the immune response during various inflammatory conditions, have received the most attention as potential enzyme suppressors (Christensen and Hermann, 2012;Christmas, 2015), but other mediators of immune responses could be of potential importance for suppressed P450 metabolism as well.…”

Section: Introductionmentioning

confidence: 99%

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis

et al. 2018

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Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)- inhibitors. CYP3A4 phenotype was measured as serum concentration of 4-hydroxycholesterol (4OHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF- inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon , interleukin (IL)-1, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF- Correlations between levels of cytokines and 4OHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF- inhibitors: i.e., IL-1ra ( = -0.408, = 0.023), IL-6 ( = -0.410, = 0.022) and CXCL8 ( = -0.403, = 0.025) ( ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF- inhibitor treatment ( > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.

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Role of Cytochrome P450s in Inflammation

Cited by 50 publications

References 152 publications

Pharmacokinetics of a modified, compounded theophylline product in dogs

Pharmacokinetics of a modified, compounded theophylline product in dogs

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging

Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis

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