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Article ; Online: APOE ε2 resilience for Alzheimer's disease is mediated by plasma lipid species: Analysis of three independent cohort studies.

Wang, Tingting / Huynh, Kevin / Giles, Corey / Mellett, Natalie A / Duong, Thy / Nguyen, Anh / Lim, Wei Ling Florence / Smith, Alex At / Olshansky, Gavriel / Cadby, Gemma / Hung, Joseph / Hui, Jennie / Beilby, John / Watts, Gerald F / Chatterjee, Pratishtha / Martins, Ian / Laws, Simon M / Bush, Ashley I / Rowe, Christopher C /

Villemagne, Victor L / Ames, David / Masters, Colin L / Taddei, Kevin / Doré, Vincent / Fripp, Jürgen / Arnold, Matthias / Kastenmüller, Gabi / Nho, Kwangsik / Saykin, Andrew J / Baillie, Rebecca / Han, Xianlin / Martins, Ralph N / Moses, Eric K / Kaddurah-Daouk, Rima / Meikle, Peter J

Alzheimer's & dementia : the journal of the Alzheimer's Association

2022 Volume 18, Issue 11, Page(s) 2151–2166

Abstract: ... cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087 ... the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384 ...

Abstract	Introduction: The apolipoprotein E (APOE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. Methods: We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087; the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819; and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. Results: A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. Individual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Discussion: Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Apolipoprotein E2/genetics ; Australia ; Apolipoproteins E/genetics ; Genotype ; Cohort Studies ; Apolipoprotein E4/genetics
Chemical Substances	Apolipoprotein E2 ; Apolipoproteins E ; Apolipoprotein E4
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12538
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Article: Differential effects on cellular iron metabolism of the physiologically relevant diatomic effector molecules, NO and CO, that bind iron.

Watts, Ralph N / Richardson, Des R

Biochimica et biophysica acta

2004 Volume 1692, Issue 1, Page(s) 1–15

Abstract: ... including S-nitrosoglutathione (GSNO), spermine-NONOate (SperNO) and S-nitroso-N-acetylpenicillamine (SNAP ...

Abstract	Both nitrogen monoxide (NO) and carbon monoxide (CO) are biologically relevant diatomic effector molecules that mediate a variety of biological functions through their avid binding to iron (Fe). Previous studies showed that NO can inhibit Fe uptake from transferrin (Tf) and increase Fe mobilisation from cells [J. Biol. Chem. 276 (2001) 4724]. We used CO gas, a CO-generating agent ([Ru(CO)3Cl2]2), and cells stably transfected with the CO-producing enzyme, haem oxygenase 1 (HO1), to assess the effect of CO on Fe metabolism. These results were compared to the effects of NO produced by a variety of NO-generating agents, including S-nitrosoglutathione (GSNO), spermine-NONOate (SperNO) and S-nitroso-N-acetylpenicillamine (SNAP). Incubation of cells with CO inhibited 59Fe uptake from 59Fe-Tf by cells, and like NO, reduced ATP levels. Hence, the ability of both agents to inhibit 59Fe uptake may be partially mediated by inhibition of energy-dependent processes. These results showing a CO-mediated decrease in 59Fe uptake from 59Fe-Tf using exogenous CO were in agreement with studies implementing cells transfected with HO1. Like NO, CO markedly prevented 59Fe uptake into ferritin. In comparison to the avid ability of exogenous CO to inhibit 59Fe uptake, it had less effect on cellular 59Fe mobilisation. Experiments with HO1-transfected cells compared to control cells showed that 59Fe mobilisation was slightly enhanced. In contrast to NO, CO did not affect the RNA-binding activity of the iron regulatory protein 1 that plays an important role in Fe homeostasis. Our studies demonstrate that subtle differences in the chemistry of NO and CO results in divergence of their ability to affect Fe metabolism.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Biological Transport ; Carbon Monoxide/metabolism ; Cell Line ; Cell Line, Tumor ; Electrophoresis, Polyacrylamide Gel ; Ferritins/metabolism ; Fibroblasts/metabolism ; Glutathione/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Heme Oxygenase-1 ; Humans ; Iron/metabolism ; Membrane Proteins ; Mice ; Nitric Oxide/metabolism ; Nitrites/metabolism ; RNA/metabolism ; Time Factors ; Transfection ; Transferrin/metabolism
Chemical Substances	Membrane Proteins ; Nitrites ; Transferrin ; Nitric Oxide (31C4KY9ESH) ; RNA (63231-63-0) ; Carbon Monoxide (7U1EE4V452) ; Adenosine Triphosphate (8L70Q75FXE) ; Ferritins (9007-73-2) ; Iron (E1UOL152H7) ; HMOX1 protein, human (EC 1.14.14.18) ; Heme Oxygenase (Decyclizing) (EC 1.14.14.18) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Hmox1 protein, mouse (EC 1.14.14.18) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2004-05-28
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbamcr.2004.02.004
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Article ; Online: Effect of Excess Iodine Intake from Iodized Salt and/or Groundwater Iodine on Thyroid Function in Nonpregnant and Pregnant Women, Infants, and Children: A Multicenter Study in East Africa.

Farebrother, Jessica / Zimmermann, Michael B / Abdallah, Fatma / Assey, Vincent / Fingerhut, Ralph / Gichohi-Wainaina, Wanjiku N / Hussein, Izzeldin / Makokha, Anselimo / Sagno, Kalil / Untoro, Juliawati / Watts, Michael / Andersson, Maria

Thyroid : official journal of the American Thyroid Association

2018 Volume 28, Issue 9, Page(s) 1198–1210

Abstract: ... only 1.6% of Djibouti salt samples (n = 1200) were adequately iodized (>15 mg/kg); (iii) the median ... iodine concentration in drinking water was 92 μg/L (IQR = 37-158 μg/L; n = 77). In all countries, UIC was ...

Abstract	Background: Acute excess iodine intake can damage the thyroid, but the effects of chronic excess iodine intake are uncertain. Few data exist for pregnant and lactating women and infants exposed to excessive iodine intake. Methods: This was a multicenter cross-sectional study. At study sites in rural Kenya and urban Tanzania previously reporting iodine excess in children, urinary iodine concentration (UIC), thyrotropin, total thyroxine, and thyroglobulin (Tg) were measured in school-age children (SAC), women of reproductive age, pregnant (PW) and lactating women, and breast-feeding and weaning infants. In a national study in Djibouti, UIC was measured in SAC and PW. At all sites, daily iodine intake was estimated based on UIC, and iodine concentration was measured in household salt and drinking water. Results: The total sample size was 4636: 1390, 2048, and 1198 subjects from Kenya, Tanzania, and Djibouti, respectively. In Kenya and Tanzania: (i) median UIC was well above thresholds for adequate iodine nutrition in all groups and exceeded the threshold for excess iodine intake in SAC; (ii) iodine concentrations >40 mg of iodine/kg were found in approximately 55% of household salt samples; (iii) iodine concentrations ≥10 μg/L were detected in 9% of drinking water samples; (iv) Tg was elevated in all population groups, but the prevalence of thyroid disorders was negligible, except that 5-12% of women of reproductive age had subclinical hyperthyroidism and 10-15% of PW were hypothyroxinemic. In Djibouti: (i) the median UIC was 335 μg/L (interquartile range [IQR] = 216-493 μg/L) in SAC and 265 μg/L (IQR = 168-449 μg/L) in PW; (ii) only 1.6% of Djibouti salt samples (n = 1200) were adequately iodized (>15 mg/kg); (iii) the median iodine concentration in drinking water was 92 μg/L (IQR = 37-158 μg/L; n = 77). In all countries, UIC was not significantly correlated with salt or water iodine concentrations. Conclusions: Although iodine intake was excessive and Tg concentrations were elevated, there was little impact on thyroid function. Chronic excess iodine intake thus appears to be well tolerated by women, infants, and children. However, such high iodine intake is unnecessary and should be avoided. Careful evaluation of contributions from both iodized salt and groundwater iodine is recommended before any review of iodization policy is considered.
MeSH term(s)	Adolescent ; Adult ; Africa, Eastern ; Child ; Cross-Sectional Studies ; Diet ; Female ; Groundwater/chemistry ; Humans ; Infant ; Infant, Newborn ; Iodine/administration & dosage ; Iodine/analysis ; Iodine/chemistry ; Pregnancy ; Sodium Chloride, Dietary ; Thyroid Gland/drug effects ; Thyroid Gland/physiology ; Young Adult
Chemical Substances	Sodium Chloride, Dietary ; iodized salt ; Iodine (9679TC07X4)
Language	English
Publishing date	2018-08-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1086044-7
ISSN	1557-9077 ; 1050-7256
ISSN (online)	1557-9077
ISSN	1050-7256
DOI	10.1089/thy.2018.0234
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Article ; Online: Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease.

Cadby, Gemma / Giles, Corey / Melton, Phillip E / Huynh, Kevin / Mellett, Natalie A / Duong, Thy / Nguyen, Anh / Cinel, Michelle / Smith, Alex / Olshansky, Gavriel / Wang, Tingting / Brozynska, Marta / Inouye, Mike / McCarthy, Nina S / Ariff, Amir / Hung, Joseph / Hui, Jennie / Beilby, John / Dubé, Marie-Pierre /

Watts, Gerald F / Shah, Sonia / Wray, Naomi R / Lim, Wei Ling Florence / Chatterjee, Pratishtha / Martins, Ian / Laws, Simon M / Porter, Tenielle / Vacher, Michael / Bush, Ashley I / Rowe, Christopher C / Villemagne, Victor L / Ames, David / Masters, Colin L / Taddei, Kevin / Arnold, Matthias / Kastenmüller, Gabi / Nho, Kwangsik / Saykin, Andrew J / Han, Xianlin / Kaddurah-Daouk, Rima / Martins, Ralph N / Blangero, John / Meikle, Peter J / Moses, Eric K

Nature communications

2022 Volume 13, Issue 1, Page(s) 3124

Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid ... ...

Abstract	We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 individuals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 individuals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P < 1 × 10
MeSH term(s)	Coronary Artery Disease/genetics ; Genetic Loci ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Homeostasis ; Humans ; Lipidomics ; Lipids ; Polymorphism, Single Nucleotide
Chemical Substances	Lipids
Language	English
Publishing date	2022-06-06
Publishing country	England
Document type	Journal Article ; Meta-Analysis ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-30875-7
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Article: The mechanism of nitrogen monoxide (NO)-mediated iron mobilization from cells. NO intercepts iron before incorporation into ferritin and indirectly mobilizes iron from ferritin in a glutathione-dependent manner.

Watts, Ralph N / Richardson, Des R

European journal of biochemistry

2002 Volume 269, Issue 14, Page(s) 3383–3392

Abstract: ... potentiated by glutathione (GSH) generated by the hexose monophosphate shunt [Watts, R.N. & Richardson, D.R ...

Abstract	Nitrogen monoxide (NO) is a cytotoxic effector molecule produced by macrophages that results in Fe mobilization from tumour target cells which inhibits DNA synthesis and mitochondrial respiration. It is well known that NO has a high affinity for Fe, and we showed that NO-mediated Fe mobilization is markedly potentiated by glutathione (GSH) generated by the hexose monophosphate shunt [Watts, R.N. & Richardson, D.R. (2001) J. Biol. Chem. 276, 4724-4732]. We hypothesized that GSH completes the coordination shell of an NO[bond]Fe complex that is released from the cell. In this report we have extended our studies to further characterize the mechanism of NO-mediated Fe mobilization. Native PAGE 59Fe-autoradiography shows that NO decreased ferritin-59Fe levels in cells prelabelled with [59Fe]transferrin. In prelabelled cells, ferritin-59Fe levels increased 3.5-fold when cells were reincubated with control media between 30 and 240 min. In contrast, when cells were reincubated with NO, ferritin-59Fe levels decreased 10-fold compared with control cells after a 240-min reincubation. However, NO could not remove Fe from ferritin in cell lysates. Our data suggest that NO intercepts 59Fe on route to ferritin, and indirectly facilitates removal of 59Fe from the protein. Studies using the GSH-depleting agent, L-buthionine-(S,R)-sulphoximine, indicated that the reduction in ferritin-59Fe levels via NO was GSH-dependent. Competition experiments with NO and permeable chelators demonstrated that both bind a similar Fe pool. We suggest that NO requires cellular metabolism in order to effect Fe mobilization and this does not occur via passive diffusion down a concentration gradient. Based on our results, we propose a model of glucose-dependent NO-mediated Fe mobilization.
MeSH term(s)	Adenocarcinoma/pathology ; Animals ; Breast Neoplasms/pathology ; Cell Membrane Permeability ; Cell-Free System ; Cytosol/metabolism ; Deferoxamine/pharmacology ; Female ; Ferritins/metabolism ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Glutathione/metabolism ; Humans ; Iron/metabolism ; Iron Chelating Agents/pharmacology ; Macrophage Activation ; Mice ; Neuroblastoma/pathology ; Neuroectodermal Tumors, Primitive, Peripheral/pathology ; Nitric Oxide/pharmacology ; Nitric Oxide Donors/pharmacology ; Nitrogen Oxides ; Oxidation-Reduction ; Penicillamine/analogs & derivatives ; Penicillamine/pharmacology ; S-Nitrosoglutathione/pharmacology ; Spermine/analogs & derivatives ; Spermine/pharmacology ; Tumor Cells, Cultured/drug effects ; Tumor Cells, Cultured/metabolism
Chemical Substances	Iron Chelating Agents ; Nitric Oxide Donors ; Nitrogen Oxides ; S-nitro-N-acetylpenicillamine ; spermine nitric oxide complex (136587-13-8) ; Spermine (2FZ7Y3VOQX) ; Nitric Oxide (31C4KY9ESH) ; S-Nitrosoglutathione (57564-91-7) ; Ferritins (9007-73-2) ; Iron (E1UOL152H7) ; Glutathione (GAN16C9B8O) ; Penicillamine (GNN1DV99GX) ; Deferoxamine (J06Y7MXW4D)
Language	English
Publishing date	2002-07
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3032-6
ISSN	1432-1033 ; 0014-2956
ISSN (online)	1432-1033
ISSN	0014-2956
DOI	10.1046/j.1432-1033.2002.02987.x
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Article ; Online: Comprehensive genetic analysis of the human lipidome identifies loci associated with lipid homeostasis with links to coronary artery disease

Gemma Cadby / Corey Giles / Phillip E. Melton / Kevin Huynh / Natalie A. Mellett / Thy Duong / Anh Nguyen / Michelle Cinel / Alex Smith / Gavriel Olshansky / Tingting Wang / Marta Brozynska / Mike Inouye / Nina S. McCarthy / Amir Ariff / Joseph Hung / Jennie Hui / John Beilby / Marie-Pierre Dubé /

Gerald F. Watts / Sonia Shah / Naomi R. Wray / Wei Ling Florence Lim / Pratishtha Chatterjee / Ian Martins / Simon M. Laws / Tenielle Porter / Michael Vacher / Ashley I. Bush / Christopher C. Rowe / Victor L. Villemagne / David Ames / Colin L. Masters / Kevin Taddei / Matthias Arnold / Gabi Kastenmüller / Kwangsik Nho / Andrew J. Saykin / Xianlin Han / Rima Kaddurah-Daouk / Ralph N. Martins / John Blangero / Peter J. Meikle / Eric K. Moses

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 17

Abstract: Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD. ...

Abstract	Dysregulation of lipid metabolism is associated with coronary artery disease (CAD). Here, the authors perform GWAS of the serum lipidome to identify variants associated with lipid species that are putatively in the mechanistic pathway to CAD.
Keywords	Science ; Q
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Adiabatic thermo-optic Mach-Zehnder switch.

Watts, Michael R / Sun, Jie / DeRose, Christopher / Trotter, Douglas C / Young, Ralph W / Nielson, Gregory N

Optics letters

2013 Volume 38, Issue 5, Page(s) 733–735

Abstract: In this Letter, we propose and demonstrate a high-speed and power-efficient thermo-optic switch using an adiabatic bend with a directly integrated silicon heater to minimize the heat capacity and therein maximize the performance of the thermo-optic ... ...

Abstract	In this Letter, we propose and demonstrate a high-speed and power-efficient thermo-optic switch using an adiabatic bend with a directly integrated silicon heater to minimize the heat capacity and therein maximize the performance of the thermo-optic switch. A rapid, τ=2.4 μs thermal time constant and a low electrical power consumption of P(π)=12.7 mW/π-phase shift were demonstrated representing a P(π)τ product of only 30.5 mW·μs in a compact device with a phase shifter of only ~10 μm long.
Language	English
Publishing date	2013-03-01
Publishing country	United States
Document type	Journal Article
ISSN	1539-4794
ISSN (online)	1539-4794
DOI	10.1364/OL.38.000733
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Article: Effects of nitrogen monoxide and carbon monoxide on molecular and cellular iron metabolism: mirror-image effector molecules that target iron.

Watts, Ralph N / Ponka, Prem / Richardson, Des R

The Biochemical journal

2003 Volume 369, Issue Pt 3, Page(s) 429–440

Abstract: Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms ... ...

Abstract	Many effector functions of nitrogen monoxide (NO) and carbon monoxide (CO) are mediated through their high-affinity for iron (Fe). In this review, the roles of NO and CO are examined in terms of their effects on the molecular and cellular mechanisms involved in Fe metabolism. Both NO and CO avidly form complexes with a plethora of Fe-containing molecules. The generation of NO and CO is mediated by the nitric oxide synthase and haem oxygenase (HO) families of enzymes respectively. The effects of NO on Fe metabolism have been well characterized, whereas knowledge of the effects of CO remains within its infancy. In terms of the role of NO in Fe metabolism, one of the best characterized interactions includes its effect on the iron regulatory proteins. These molecules are mRNA-binding proteins that control the expression of the transferrin receptor 1 and ferritin, molecules that are involved in Fe uptake and storage respectively. Apart from this, activated macrophages impart their cytotoxic activity by generating NO, which results in marked Fe mobilization from tumour-cell targets. This deprives the cell of the Fe that is required for DNA synthesis and energy production. Considering that HO degrades haem, resulting in the release of CO, Fe(II) and biliverdin, it is suggested that a CO-Fe complex will form. This may account for the rapid Fe mobilization observed from macrophages after haemoglobin catabolism. Intriguingly, overexpression of HO results in cellular Fe mobilization, suggesting that CO has a similar effect to NO on Fe trafficking. Preliminary evidence suggests that, like NO, CO plays important roles in Fe metabolism.
MeSH term(s)	Animals ; Carbon Monoxide/metabolism ; Heme Oxygenase (Decyclizing)/metabolism ; Heme Oxygenase-1 ; Humans ; Iron/metabolism ; Membrane Proteins ; Nitric Oxide/metabolism ; Nitric Oxide Synthase/metabolism
Chemical Substances	Membrane Proteins ; Nitric Oxide (31C4KY9ESH) ; Carbon Monoxide (7U1EE4V452) ; Iron (E1UOL152H7) ; Nitric Oxide Synthase (EC 1.14.13.39) ; HMOX1 protein, human (EC 1.14.14.18) ; Heme Oxygenase (Decyclizing) (EC 1.14.14.18) ; Heme Oxygenase-1 (EC 1.14.14.18)
Language	English
Publishing date	2003-02-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0264-6021 ; 0006-2936 ; 0306-3275
ISSN (online)	1470-8728
ISSN	0264-6021 ; 0006-2936 ; 0306-3275
DOI	10.1042/BJ20021302
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Article: Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1.

Watts, Ralph N / Hawkins, Clare / Ponka, Prem / Richardson, Des R

Proceedings of the National Academy of Sciences of the United States of America

2006 Volume 103, Issue 20, Page(s) 7670–7675

Abstract: Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS- ...

Abstract	Nitrogen monoxide (NO) plays a role in the cytotoxic mechanisms of activated macrophages against tumor cells by inducing iron (Fe) release. We have shown that NO-mediated Fe efflux from cells required glutathione (GSH), and we have hypothesized that a GS-Fe-NO complex was released. Hence, we studied the role of the GSH-conjugate transporter multidrug resistance-associated protein 1 (MRP1) in NO-mediated Fe efflux. MCF7-VP cells overexpressing MRP1 exhibited a 3- to 4-fold increase in NO-mediated 59Fe and GSH efflux compared with WT cells (MCF7-WT) over 4 h. Similar results were found for other MRP1-overexpressing cell types but not those expressing another drug efflux pump, P-glycoprotein. NO-mediated 59Fe and GSH efflux were temperature- and energy-dependent and were significantly decreased by the GSH-depleting agent and MRP1 transport inhibitor L-buthionine-[S,R]-sulfoximine. Other MRP1 inhibitors, MK571, probenecid, and difloxacin, significantly inhibited NO-mediated 59Fe release. EPR spectroscopy demonstrated the dinitrosyl-dithiol-Fe complex (DNIC) peak in NO-treated cells was increased by MRP1 inhibitors, indicating inhibited DNIC transport from cells. The extent of DNIC accumulation correlated with the ability of MRP1 inhibitors to prevent NO-mediated 59Fe efflux. MCF7-VP cells were more sensitive than MCF7-WT cells to growth inhibition by effects of NO, which was potentiated by L-buthionine-[S,R]-sulfoximine. These data indicate the importance of GSH in NO-mediated inhibition of proliferation. Collectively, NO stimulates Fe and GSH efflux from cells via MRP1. Active transport of NO by MRP1 overcomes diffusion that is inefficient and nontargeted, which has broad ramifications for understanding NO biology.
MeSH term(s)	ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Adenosine Triphosphate/metabolism ; Animals ; Buthionine Sulfoximine/metabolism ; Cell Line ; Cell Proliferation ; Enzyme Inhibitors/metabolism ; Glutathione/metabolism ; Humans ; Iron/metabolism ; Iron Radioisotopes/metabolism ; Mice ; Nitric Oxide/metabolism ; Nitric Oxide Donors/metabolism ; Nitrogen Oxides/metabolism ; Spermine/analogs & derivatives ; Spermine/metabolism ; Temperature ; Transferrin/metabolism
Chemical Substances	ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Enzyme Inhibitors ; Iron Radioisotopes ; Nitric Oxide Donors ; Nitrogen Oxides ; Transferrin ; spermine nitric oxide complex (136587-13-8) ; Spermine (2FZ7Y3VOQX) ; Nitric Oxide (31C4KY9ESH) ; Buthionine Sulfoximine (5072-26-4) ; Adenosine Triphosphate (8L70Q75FXE) ; Iron (E1UOL152H7) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2006-05-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.0602515103
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: The mechanism of nitrogen monoxide (NO)‐mediated iron mobilization from cells: NO intercepts iron before incorporation into ferritin and indirectly mobilizes iron from ferritin in a glutathione‐dependent manner

Watts, Ralph N / Richardson, Des R

European journal of biochemistry. 2002 July, v. 269, no. 14

2002

Abstract: ... potentiated by glutathione (GSH) generated by the hexose monophosphate shunt [Watts, R.N. & Richardson, D.R ...

Abstract	Nitrogen monoxide (NO) is a cytotoxic effector molecule produced by macrophages that results in Fe mobilization from tumour target cells which inhibits DNA synthesis and mitochondrial respiration. It is well known that NO has a high affinity for Fe, and we showed that NO‐mediated Fe mobilization is markedly potentiated by glutathione (GSH) generated by the hexose monophosphate shunt [Watts, R.N. & Richardson, D.R. (2001) J. Biol. Chem. 276, 4724–4732]. We hypothesized that GSH completes the coordination shell of an NO–Fe complex that is released from the cell. In this report we have extended our studies to further characterize the mechanism of NO‐mediated Fe mobilization. Native PAGE 59Fe‐autoradiography shows that NO decreased ferritin‐59Fe levels in cells prelabelled with [59Fe]transferrin. In prelabelled cells, ferritin‐59Fe levels increased 3.5−fold when cells were reincubated with control media between 30 and 240 min. In contrast, when cells were reincubated with NO, ferritin‐59Fe levels decreased 10‐fold compared with control cells after a 240‐min reincubation. However, NO could not remove Fe from ferritin in cell lysates. Our data suggest that NO intercepts 59Fe on route to ferritin, and indirectly facilitates removal of 59Fe from the protein. Studies using the GSH‐depleting agent, l‐buthionine‐(S,R)‐sulphoximine, indicated that the reduction in ferritin‐59Fe levels via NO was GSH‐dependent. Competition experiments with NO and permeable chelators demonstrated that both bind a similar Fe pool. We suggest that NO requires cellular metabolism in order to effect Fe mobilization and this does not occur via passive diffusion down a concentration gradient. Based on our results, we propose a model of glucose‐dependent NO‐mediated Fe mobilization.
Keywords	DNA ; chelating agents ; cytotoxicity ; ferritin ; glutathione ; iron ; macrophages ; metabolism ; models ; neoplasms ; nitric oxide ; polyacrylamide gel electrophoresis ; transferrin
Language	English
Dates of publication	2002-07
Size	p. 3383-3392.
Publishing place	Blackwell Science Ltd
Document type	Article
ZDB-ID	3032-6
ISSN	1432-1033 ; 0014-2956
ISSN (online)	1432-1033
ISSN	0014-2956
DOI	10.1046/j.1432-1033.2002.02987.x
Database	NAL-Catalogue (AGRICOLA)

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