Regulation of Cytochrome P450 4F11 by Nuclear Transcription Factor-κB

Bell, Jordan; Strobel, Henry W.

doi:10.1124/dmd.111.041178

Cited by 16 publications

(8 citation statements)

References 18 publications

(29 reference statements)

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“…Therefore, the human P450 4F12 gene is most likely regulated by PXR, indicating the possibility that P450 4F12 induction by PXR ligands leads to drug-drug interactions toward the metabolism of P450 4F12 substrates (e.g., ebastine, astemizole, and terfenadine). In addition, P450 4F11 gene expression is also negatively regulated by nuclear factor kB in the human liver carcinoma cell line (HepG2) (Bell and Strobel, 2012). These results, together with the similar P450 4F mRNA distribution between marmosets and humans, suggest that marmosets and humans share, at least partly, transcriptional regulation and induction of P450 4F genes.…”

Section: Tablesupporting

confidence: 55%

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Uehara

Uno

Yuki

et al. 2016

Drug Metabolism and Disposition

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Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the v-hydroxylation of leukotriene B 4 . In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/ cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

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Section: Tablesupporting

confidence: 55%

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Uehara

Uno

Yuki

et al. 2016

Drug Metabolism and Disposition

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“…One explanation is that cytokine expression and proinflammatory oxylipid biosynthesis may form negative feedback loops with each other. Expression of epoxygenase enzymes, for example, can be suppressed by TNF-α (Bell, 2011;Bell and Strobel, 2012). Another possibility is that certain oxylipids may be more effective in controlling leukocyte inflammatory responses than other lipid mediators within the profile.…”

Section: Discussionmentioning

confidence: 99%

Association between polyunsaturated fatty acid-derived oxylipid biosynthesis and leukocyte inflammatory marker expression in periparturient dairy cows

Raphael

Halbert

Contreras

et al. 2014

Journal of Dairy Science

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Peripheral blood mononuclear leukocytes from periparturient cows can have exacerbated inflammatory responses that contribute to disease incidence and severity. Oxylipids derived from the oxygenation of polyunsaturated fatty acids (PUFA) can regulate the magnitude and duration of inflammation. Although PUFA substrate for oxylipid biosynthesis in leukocytes is known to change across the periparturient period, the plasma oxylipid profile and how this profile relates to leukocyte inflammatory phenotype is not clear. The objective of this study was to determine if a relationship exists between the profile of pro- and antiinflammatory plasma oxylipids and the inflammatory phenotype of peripheral blood leukocytes during the periparturient period. Seven multiparous Holsteins were sampled from the prepartum period through peak lactation. Plasma oxylipids were measured by liquid chromatography-mass spectrometry, peripheral leukocyte mRNA expression was measured by quantitative PCR, and PUFA content of peripheral blood mononuclear cells was measured by gas chromatography-mass spectrometry. Concentrations of several hydroxyl products of linoleic and arachidonic acid changed over time. Linoleic acid and arachidonic acid concentrations in leukocytes increased during early lactation, suggesting that substrate availability for hydroxyoctadecadienoic and hydroxyeicosatetraenoic acid biosynthesis may influence the oxylipid profile. Leukocyte mRNA expressions of IL-12B, IL-1B, inducible nitric oxide synthase 2, and cyclooxygenase 2 were correlated with several plasma oxylipids. These are the first observations linking leukocyte inflammatory gene responses to shifts in oxylipid biosynthesis in periparturient dairy cows.

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“…Underexpression of EPHX1 is frequently described in COPD airway and lung tissues, and "slow" EPHX1 SNPs are associated with impaired enzyme activity and increased COPD risk, and "fast" SNPs potentially confer a protective effect (40). Cytochrome P450 4F enzymes, such as CYP4F11, are involved in cellular protection, xenobiotic metabolism, detoxification, lipid synthesis, and metabolic activation of drugs, including those used to treat chronic inflammatory disease (63,64). They also have a direct role in inhibiting inflammation through suppression of leukotriene and prostaglandin signals (64).…”

Section: Original Researchmentioning

confidence: 99%

“…However, regulation of CYP4F11 in an environment of chronic inflammation is complex. In human epidermal keratinocytes, although TNF-a leads to immediate activation of CYP4F11 through JNK, subsequent activation of NF-kb results in direct inhibition of CYP4F11 (63,64). CYP4F11 regulators are clearly important to COPD biology, although little is known about the function of this enzyme in respiratory tissues.…”

Section: Original Researchmentioning

confidence: 99%

DNA Methylation Is Globally Disrupted and Associated with Expression Changes in Chronic Obstructive Pulmonary Disease Small Airways

Vucic

Chari

Thu

et al. 2014

Am J Respir Cell Mol Biol

126

110

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DNA methylation is an epigenetic modification that is highly disrupted in response to cigarette smoke and involved in a wide spectrum of malignant and nonmalignant diseases, but surprisingly not previously assessed in small airways of patients with chronic obstructive pulmonary disease (COPD). Small airways are the primary sites of airflow obstruction in COPD. We sought to determine whether DNA methylation patterns are disrupted in small airway epithelia of patients with COPD, and evaluate whether changes in gene expression are associated with these disruptions. Genome-wide methylation and gene expression analysis were performed on small airway epithelial DNA and RNA obtained from the same patient during bronchoscopy, using Illumina's Infinium HM27 and Affymetrix's Genechip Human Gene 1.0 ST arrays. To control for known effects of cigarette smoking on DNA methylation, methylation and gene expression profiles were compared between former smokers with and without COPD matched for age, pack-years, and years of smoking cessation. Our results indicate that aberrant DNA methylation is (1) a genome-wide phenomenon in small airways of patients with COPD, and (2) associated with altered expression of genes and pathways important to COPD, such as the NF-E2-related factor 2 oxidative response pathway. DNA methylation is likely an important mechanism contributing to modulation of genes important to COPD pathology. Because these methylation events may underlie disease-specific gene expression changes, their characterization is a critical first step toward the development of epigenetic markers and an opportunity for developing novel epigenetic therapeutic interventions for COPD.

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Regulation of Cytochrome P450 4F11 by Nuclear Transcription Factor-κB

Abstract: ABSTRACT:Although the mechanisms that regulate CYP4F genes have been and are currently being studied in a number of laboratories, the specific mechanisms for the regulation of these genes are not yet fully understood. This study shows that nuclear factor

Cited by 16 publications

References 18 publications

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Association between polyunsaturated fatty acid-derived oxylipid biosynthesis and leukocyte inflammatory marker expression in periparturient dairy cows

DNA Methylation Is Globally Disrupted and Associated with Expression Changes in Chronic Obstructive Pulmonary Disease Small Airways

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