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Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.
Manousaki D, Dudding T, Haworth S, Hsu YH, Liu CT, Medina-Gómez C, Voortman T, van der Velde N, Melhus H, Robinson-Cohen C, Cousminer DL, Nethander M, Vandenput L, Noordam R, Forgetta V, Greenwood CMT, Biggs ML, Psaty BM, Rotter JI, Zemel BS, Mitchell JA, Taylor B, Lorentzon M, Karlsson M, Jaddoe VVW, Tiemeier H, Campos-Obando N, Franco OH, Utterlinden AG, Broer L, van Schoor NM, Ham AC, Ikram MA, Karasik D, de Mutsert R, Rosendaal FR, den Heijer M, Wang TJ, Lind L, Orwoll ES, Mook-Kanamori DO, Michaëlsson K, Kestenbaum B, Ohlsson C, Mellström D, de Groot LCPGM, Grant SFA, Kiel DP, Zillikens MC, Rivadeneira F, Sawcer S, Timpson NJ, Richards JB
(2017) Am J Hum Genet 101: 227-238
MeSH Terms: Cholestanetriol 26-Monooxygenase, Cytochrome P450 Family 2, Gene Frequency, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Humans, Multiple Sclerosis, Polymorphism, Single Nucleotide, Risk Factors, Vitamin D, Vitamin D Deficiency
Show Abstract · Added September 19, 2017
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Human mitochondrial cytochrome P450 27C1 is localized in skin and preferentially desaturates -retinol to 3,4-dehydroretinol.
Johnson KM, Phan TTN, Albertolle ME, Guengerich FP
(2017) J Biol Chem 292: 13672-13687
MeSH Terms: Biocatalysis, Cytochrome P450 Family 27, Diterpenes, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Humans, Hydrogenation, Hydroxylation, Isoenzymes, Kinetics, Mitochondria, Molecular Structure, Organ Specificity, Oxidation-Reduction, Peptide Fragments, Proteolysis, Proteomics, Skin, Stereoisomerism, Substrate Specificity, Vitamin A
Show Abstract · Added March 14, 2018
Recently, zebrafish and human cytochrome P450 (P450) 27C1 enzymes have been shown to be retinoid 3,4-desaturases. The enzyme is unusual among mammalian P450s in that the predominant oxidation is a desaturation and in that hydroxylation represents only a minor pathway. We show by proteomic analysis that P450 27C1 is localized to human skin, with two proteins of different sizes present, one being a cleavage product of the full-length form. P450 27C1 oxidized all--retinol to 3,4-dehydroretinol, 4-hydroxy (OH) retinol, and 3-OH retinol in a 100:3:2 ratio. Neither 3-OH nor 4-OH retinol was an intermediate in desaturation. No kinetic burst was observed in the steady state; neither the rate of substrate binding nor product release was rate-limiting. Ferric P450 27C1 reduction by adrenodoxin was 3-fold faster in the presence of the substrate and was ∼5-fold faster than the overall turnover. Kinetic isotope effects of 1.5-2.3 (on / ) were observed with 3,3-, 4,4-, and 3,3,4,4-deuterated retinol. Deuteration at C-4 produced a 4-fold increase in 3-hydroxylation due to metabolic switching, with no observable effect on 4-hydroxylation. Deuteration at C-3 produced a strong kinetic isotope effect for 3-hydroxylation but not 4-hydroxylation. Analysis of the products of deuterated retinol showed a lack of scrambling of a putative allylic radical at C-3 and C-4. We conclude that the most likely catalytic mechanism begins with abstraction of a hydrogen atom from C-4 (or possibly C-3) initiating the desaturation pathway, followed by a sequential abstraction of a hydrogen atom or proton-coupled electron transfer. Adrenodoxin reduction and hydrogen abstraction both contribute to rate limitation.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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21 MeSH Terms
Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans.
Gangadhariah MH, Dieckmann BW, Lantier L, Kang L, Wasserman DH, Chiusa M, Caskey CF, Dickerson J, Luo P, Gamboa JL, Capdevila JH, Imig JD, Yu C, Pozzi A, Luther JM
(2017) Diabetologia 60: 1066-1075
MeSH Terms: Animals, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Eicosanoids, Insulin Resistance, Islets of Langerhans, Male, Mesenteric Arteries, Mice
Show Abstract · Added April 26, 2017
AIMS/HYPOTHESIS - Insulin resistance is frequently associated with hypertension and type 2 diabetes. The cytochrome P450 (CYP) arachidonic acid epoxygenases (CYP2C, CYP2J) and their epoxyeicosatrienoic acid (EET) products lower blood pressure and may also improve glucose homeostasis. However, the direct contribution of endogenous EET production on insulin sensitivity has not been previously investigated. In this study, we tested the hypothesis that endogenous CYP2C-derived EETs alter insulin sensitivity by analysing mice lacking CYP2C44, a major EET producing enzyme, and by testing the association of plasma EETs with insulin sensitivity in humans.
METHODS - We assessed insulin sensitivity in wild-type (WT) and Cyp2c44 mice using hyperinsulinaemic-euglycaemic clamps and isolated skeletal muscle. Insulin secretory function was assessed using hyperglycaemic clamps and isolated islets. Vascular function was tested in isolated perfused mesenteric vessels. Insulin sensitivity and secretion were assessed in humans using frequently sampled intravenous glucose tolerance tests and plasma EETs were measured by mass spectrometry.
RESULTS - Cyp2c44 mice showed decreased glucose tolerance (639 ± 39.5 vs 808 ± 37.7 mmol/l × min for glucose tolerance tests, p = 0.004) and insulin sensitivity compared with WT controls (hyperinsulinaemic clamp glucose infusion rate average during terminal 30 min 0.22 ± 0.02 vs 0.33 ± 0.01 mmol kg min in WT and Cyp2c44 mice respectively, p = 0.003). Although glucose uptake was diminished in Cyp2c44 mice in vivo (gastrocnemius R 16.4 ± 2.0 vs 6.2 ± 1.7 μmol 100 g min, p < 0.01) insulin-stimulated glucose uptake was unchanged ex vivo in isolated skeletal muscle. Capillary density was similar but vascular K-induced relaxation was impaired in isolated Cyp2c44 vessels (maximal response 39.3 ± 6.5% of control, p < 0.001), suggesting that impaired vascular reactivity produces impaired insulin sensitivity in vivo. Similarly, plasma EETs positively correlated with insulin sensitivity in human participants.
CONCLUSIONS/INTERPRETATION - CYP2C-derived EETs contribute to insulin sensitivity in mice and in humans. Interventions to increase circulating EETs in humans could provide a novel approach to improve insulin sensitivity and treat hypertension.
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3 Members
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9 MeSH Terms
Human cytochrome P450 27C1 catalyzes 3,4-desaturation of retinoids.
Kramlinger VM, Nagy LD, Fujiwara R, Johnson KM, Phan TT, Xiao Y, Enright JM, Toomey MB, Corbo JC, Guengerich FP
(2016) FEBS Lett 590: 1304-12
MeSH Terms: Cytochrome P450 Family 27, Humans, Retinoids
Show Abstract · Added March 14, 2018
In humans, a considerable fraction of the retinoid pool in skin is derived from vitamin A2 (all-trans 3,4-dehydroretinal). Vitamin A2 may be locally generated by keratinocytes, which can convert vitamin A1 (all-trans retinol) into vitamin A2 in cell culture. We report that human cytochrome P450 (hP450) 27C1, a previously 'orphan' enzyme, can catalyze this reaction. Purified recombinant hP450 27C1 bound and desaturated all-trans retinol, retinal, and retinoic acid, as well as 11-cis-retinal. Although the physiological role of 3,4-dehydroretinoids in humans is unclear, we have identified hP450 27C1 as an enzyme capable of efficiently mediating their formation.
© 2016 Federation of European Biochemical Societies.
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1 Members
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3 MeSH Terms
Oxidation of endogenous N-arachidonoylserotonin by human cytochrome P450 2U1.
Siller M, Goyal S, Yoshimoto FK, Xiao Y, Wei S, Guengerich FP
(2014) J Biol Chem 289: 10476-10487
MeSH Terms: Amino Acid Sequence, Animals, Arachidonic Acids, Brain, Catalysis, Cattle, Chromatography, Liquid, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Erythrocytes, Escherichia coli, Gene Expression Regulation, Enzymologic, Humans, Indoles, Liver, Magnetic Resonance Spectroscopy, Mass Spectrometry, Molecular Sequence Data, Oxygen, Polymerase Chain Reaction, Protein Binding, Proteomics, Sequence Homology, Amino Acid, Serotonin
Show Abstract · Added March 10, 2014
Cytochrome P450 (P450) 2U1 has been shown to be expressed, at the mRNA level, in human thymus, brain, and several other tissues. Recombinant P450 2U1 was purified and used as a reagent in a metabolomic search for substrates in bovine brain. In addition to fatty acid oxidation reactions, an oxidation of endogenous N-arachidonoylserotonin was characterized. Subsequent NMR and mass spectrometry and chemical synthesis showed that the main product was the result of C-2 oxidation of the indole ring, in contrast to other human P450s that generated different products. N-Arachidonoylserotonin, first synthesized chemically and described as an inhibitor of fatty acid amide hydrolase, had previously been found in porcine and mouse intestine; we demonstrated its presence in bovine and human brain samples. The product (2-oxo) was 4-fold less active than N-arachidonoylserotonin in inhibiting fatty acid amide hydrolase. The rate of oxidation of N-arachidonoylserotonin was similar to that of arachidonic acid, one of the previously identified fatty acid substrates of P450 2U1. The demonstration of the oxidation of N-arachidonoylserotonin by P450 2U1 suggests a possible role in human brain and possibly other sites.
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2 Members
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24 MeSH Terms
The Cyp2c44 epoxygenase regulates epithelial sodium channel activity and the blood pressure responses to increased dietary salt.
Capdevila JH, Pidkovka N, Mei S, Gong Y, Falck JR, Imig JD, Harris RC, Wang W
(2014) J Biol Chem 289: 4377-86
MeSH Terms: Animals, Blood Pressure, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Epithelial Sodium Channels, Humans, Hypertension, Kidney, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 3, Phosphorylation, Sodium Chloride, Dietary
Show Abstract · Added January 28, 2014
Hypertension is a major risk factor for cerebral, cardiovascular, and renal disease, and its prevalence and devastating consequences raises a need for new strategies for its early diagnosis and treatment. We show here that lack of a Cyp2c44 epoxygenase causes dietary salt-sensitive hypertension, a common form of the human disease. Cyp2c44(-/-) mice on normal salt diets are normotensive but become hypertensive when fed high salt. Hypertensive Cyp2c44(-/-) mice show a hyperactive kidney epithelial sodium channel (ENaC) and reductions in ERK1/2 and ENaC subunit phosphorylation. The demonstration that amiloride, an ENaC inhibitor, lowers the blood pressure of hypertensive Cyp2c44(-/-) mice identifies a role for the channel in the hypertensive phenotype of the animals. These studies: (a) identify an antihypertensive role for the kidney Cyp2c44 epoxygenase and for its epoxyeicosatrienoic acid (EET) metabolites in the in vivo control of ENaC activity and the activation of mitogenic kinase pathways; (b) provide evidence for a Cyp2c44 epoxygenase, EET-mediated mechanism of ENaC regulation involving an ERK1/2-catalyzed threonine phosphorylation of the channel γ subunit: and (c) characterize a common scientific platform that could explain the seemingly unrelated biological activities attributed to the epoxygenase metabolites in cell proliferation, angiogenesis, channel activity, and blood pressure control. It is expected that these results will serve as a basis for the development of novel strategies for the early diagnosis and treatment of hypertension and of pathophysiologies associated with dysfunctional mitogenic signaling.
1 Communities
1 Members
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13 MeSH Terms
PPARα activation can help prevent and treat non-small cell lung cancer.
Skrypnyk N, Chen X, Hu W, Su Y, Mont S, Yang S, Gangadhariah M, Wei S, Falck JR, Jat JL, Zent R, Capdevila JH, Pozzi A
(2014) Cancer Res 74: 621-31
MeSH Terms: Animals, Arachidonic Acids, Bezafibrate, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Disease Models, Animal, Endothelial Cells, Female, Gene Expression Regulation, Neoplastic, Humans, Lung Neoplasms, Male, Mice, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, PPAR alpha, Pyrimidines
Show Abstract · Added February 25, 2014
Non-small cell lung cancer (NSCLC) not amenable to surgical resection has a high mortality rate, due to the ineffectiveness and toxicity of chemotherapy. Thus, there remains an urgent need of efficacious drugs that can combat this disease. In this study, we show that targeting the formation of proangiogenic epoxyeicosatrienoic acids (EET) by the cytochrome P450 arachidonic acid epoxygenases (Cyp2c) represents a new and safe mechanism to treat NSCLC growth and progression. In the transgenic murine K-Ras model and human orthotopic models of NSCLC, we found that Cyp2c44 could be downregulated by activating the transcription factor PPARα with the ligands bezafibrate and Wyeth-14,643. Notably, both treatments reduced primary and metastatic NSCLC growth, tumor angiogenesis, endothelial Cyp2c44 expression, and circulating EET levels. These beneficial effects were independent of the time of administration, whether before or after the onset of primary NSCLC, and they persisted after drug withdrawal, suggesting the benefits were durable. Our findings suggest that strategies to downregulate Cyp2c expression and/or its enzymatic activity may provide a safer and effective strategy to treat NSCLC. Moreover, as bezafibrate is a well-tolerated clinically approved drug used for managing lipidemia, our findings provide an immediate cue for clinical studies to evaluate the utility of PPARα ligands as safe agents for the treatment of lung cancer in humans.
1 Communities
5 Members
1 Resources
21 MeSH Terms
Role of epoxyeicosatrienoic acids (EETs) in mediation of dopamine's effects in the kidney.
Zhang MZ, Wang Y, Yao B, Gewin L, Wei S, Capdevila JH, Harris RC
(2013) Am J Physiol Renal Physiol 305: F1680-6
MeSH Terms: Animals, Arachidonic Acid, Aromatic-L-Amino-Acid Decarboxylases, Catechol O-Methyltransferase, Cells, Cultured, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Diet, Sodium-Restricted, Dihydroxyphenylalanine, Disease Models, Animal, Diuresis, Dopamine, Dopamine Agents, Hypertension, Kidney, Male, Mice, Mice, Knockout, Natriuresis, Sodium Chloride, Dietary
Show Abstract · Added February 26, 2014
We have recently demonstrated that intrarenal dopamine plays an important role in preventing the development of systemic hypertension. Similarly, renal cytochrome P-450 (CYP)-epoxygenase-derived arachidonic acid metabolites, epoxyeicosatrienoic acids (EETs), also are antihypertensive through inhibiting sodium reabsorption and vasodilation. The potential interaction between renal dopamine and epoxygenase systems was investigated. Catechol-O-methyl-transferase (COMT)(-/-) mice with increased intrarenal dopamine levels and proximal tubule deletion of aromatic amino acid decarboxylase (ptAADC(-/-)) mice with renal dopamine deficiency were treated with a low-salt diet or high-salt diet for 2 wk. Wild-type or Cyp2c44(-/-) mice were treated with gludopa, which selectively increased renal dopamine levels. In low salt-treated mice, urinary EET levels were related to renal dopamine levels, being highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. In high salt-treated mice, total EET and individual EET levels in both the kidney and urine were also highest in COMT(-/-) mice and lowest in ptAADC(-/-) mice. Selective increases in renal dopamine in response to gludopa administration led to marked increases in both total and all individual EET levels in the kidney without any changes in blood levels. qRT-PCR and immunoblotting indicated that gludopa increased renal Cyp2c44 mRNA and protein levels. Gludopa induced marked increases in urine volume and urinary sodium excretion in wild-type mice. In contrast, gludopa did not induce significant increases in urine volume or urinary sodium excretion in Cyp2c44(-/-) mice. These studies demonstrate that renal EET levels are maintained by intrarenal dopamine, and Cyp2c44-derived EETs play an important role in intrarenal dopamine-induced natriuresis and diuresis.
1 Communities
4 Members
0 Resources
20 MeSH Terms
Epoxyeicosatrienoic acids (EETs) regulate epithelial sodium channel activity by extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated phosphorylation.
Pidkovka N, Rao R, Mei S, Gong Y, Harris RC, Wang WH, Capdevila JH
(2013) J Biol Chem 288: 5223-31
MeSH Terms: 8,11,14-Eicosatrienoic Acid, Animals, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Antihypertensive Agents, Cetuximab, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, Epidermal Growth Factor, Epithelial Sodium Channels, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Humans, Hypertension, Kidney, Male, Mice, Models, Biological, Phosphorylation
Show Abstract · Added August 19, 2013
The epithelial sodium channel (ENaC) participates in the regulation of plasma sodium and volume, and gain of function mutations in the human channel cause salt-sensitive hypertension. Roles for the arachidonic acid epoxygenase metabolites, the epoxyeicosatrienoic acids (EETs), in ENaC activity have been identified; however, their mechanisms of action remain unknown. In polarized M1 cells, 14,15-EET inhibited amiloride-sensitive apical to basolateral sodium transport as effectively as epidermal growth factor (EGF). The EET effects were associated with increased threonine phosphorylation of the ENaC β and γ subunits and abolished by inhibitors of (a) mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal regulated kinases 1 and 2 (MEK/ERK1/2) and (b) EGF receptor signaling. CYP2C44 epoxygenase knockdown blunted the sodium transport effects of EGF, and its 14,15-EET metabolite rescued the knockdown phenotype. The relevance of these findings is indicated by (a) the hypertension that results in mice administered cetuximab, an inhibitor of EGF receptor binding, and (b) immunological data showing an association between the pressure effects of cetuximab and reductions in ENaCγ phosphorylation. These studies (a) identify an ERK1/2-dependent mechanism for ENaC inhibition by 14,15-EET, (b) point to ENaC as a proximal target for EET-activated ERK1/2 mitogenic kinases, (c) characterize a mechanistic commonality between EGF and epoxygenase metabolites as ENaC inhibitors, and (d) suggest a CYP2C epoxygenase-mediated pathway for the regulation of distal sodium transport.
1 Communities
1 Members
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19 MeSH Terms
Bioactivation of fluorinated 2-aryl-benzothiazole antitumor molecules by human cytochrome P450s 1A1 and 2W1 and deactivation by cytochrome P450 2S1.
Wang K, Guengerich FP
(2012) Chem Res Toxicol 25: 1740-51
MeSH Terms: Antineoplastic Agents, Benzothiazoles, Biocatalysis, Chromatography, High Pressure Liquid, Cytochrome P-450 CYP1A1, Cytochrome P-450 Enzyme System, Cytochrome P450 Family 2, DNA Adducts, Humans, Kinetics, Microsomes, Liver, Oxidation-Reduction, Spectrometry, Mass, Electrospray Ionization, Thiazoles
Show Abstract · Added March 7, 2014
Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of 5F 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and the formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two-step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O-demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity.
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14 MeSH Terms