A glance at…antioxidant and antiinflammatory properties of dietary cobalt

Nutrition 46 (2018) 62–66

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Nutrition and food

A glance at.antioxidant and antiinflammatory properties of dietary cobalt Michael J. Glade Ph.D. a, *, Michael M. Meguid M.D., Ph.D. b a

The Nutrition Doctor, Kailua-Kona, Hawaii, USA Professor Emeritus, Surgery, Neuroscience and Nutrition, Department of Surgery, University Hospital, Upstate Medical University, Syracuse, New York, USA b

Cobalt: an underappreciated dietary essential Cobalt is a transition metal that is distributed throughout the environment [1]. It is the 33rd most abundant element in the earth’s crust [2] and constitutes 0.001% of the earth’s crust [1]. Commercially, cobalt ions (Coþ2) are separated from linnaeite (Co3 S4), carrolite (CuCo2 S4), safflorite (CoAs2), skutterudite (CoAs3), erythrite (Co3[AsO4]2), and glaucodot (CoAsS) [2]. Within the human food supply, Coþ2 that are not associated with vitamin B12 molecules occur in inorganic forms (e.g., CoCl2, CoCl2[H20]6, CoSO4, CoCO3) [1,2] and are especially abundant in fish, nuts, green leafy vegetables, and greens [1]. In the eyes of regulatory agencies, dietary requirements for cobalt are considered to be determined by dietary requirements for vitamin B12 [1,3], reflecting a complete reliance on determinations of vitamin B12 status to determine cobalt status, to the exclusion of the possibility that cobalt may play important biological roles independent of and in addition to its sequestration within vitamin B12 molecules. Most consumed Coþ2 is not associated with vitamin B12; for example, in the United States, vitamin B12-bound Coþ2 accounts for 2% to 3% of total daily Coþ2 intake [4] and in Japan, vitamin B12-bound Coþ2 accounts for about 10% of total daily Coþ2 intake [5]. Because Coþ2 is not released from vitamin B12 during the absorption of the vitamin, the efficiency of absorption of vitamin B12-associated Coþ2 is the same as the efficiency of absorption of vitamin B12 [6–14], which ranges from 60% to 97% in adults [11]. The gastrointestinal absorption of inorganic Coþ2 is somewhat less efficient; for example, from 9% to 66% of ingested CoCl2 is taken up by intestinal cells and transferred into the human bloodstream by ferroportin [2,15–17]. In humans, 99% of non-vitamin B12–associated Coþ2 circulates bound to proteins (predominantly albumin and transferrin) [15, 18]. Circulating concentrations of non-vitamin B12–associated Coþ2 are proportional to non-vitamin B12–associated Coþ2 intakes [16,19–21]. Renal clearance of Coþ2 ions is proportional to * Corresponding author. Tel.: þ1-847-329-9818. E-mail address: [email protected] (M. J. Glade). https://doi.org/10.1016/j.nut.2017.08.009 0899-9007/Ó 2017 Elsevier Inc. All rights reserved.

the serum Coþ2 [20], renal reabsorption of Coþ2 ions is inversely proportional to Coþ2 intake [22], and circulating Coþ2 is proportional to total Coþ2 intakes [19,20]; therefore, renal clearance of Coþ2 ions is proportional to Coþ2 intake [19–22]. Although renal clearance of Coþ2 ions is proportional to Coþ2 intake [19–22], tissue content of Coþ2 ions increases with rising Coþ2 intake [22], with whole-body Coþ2 retention averaging about 1.5% of Coþ2 intake daily [22].

Cobalt and heme degradation Cobalt stimulates the detoxification of heme [23–44]. Hemoglobin (Hb) and free heme are released when red blood cells are lysed; Hb rapidly associates with circulating haptoglobin (Hp; secreted by hepatocytes [23]), forming haptoglobin: hemoglobin (Hp:Hb) complexes, and heme associates with circulating hemopexin (Hx), forming hemopexin:heme (Hx:heme) complexes [23,24]. In the circulation, the formation of intravascular Hp:Hb complexes protect local endothelial and other tissues from ferrous ion (Feþ2)-induced oxidative “hot spots” [23]. Hp:Hb complexes bind to CD163 surface receptors on monocytes and macrophages, whereas Hx:heme complexes bind to CD91 surface receptors on monocytes and macrophages [24]. Hp:Hb and Hx:heme complexes are internalized by receptormediated endocytosis during the formation of cytoplasmic endosomes [23,24]. After sequestration into cytoplasmic endosomes, CD163 and CD91 receptors are released and recycled to the cell membranes, heme is released from Hx:heme, Hp:Hb, Hx and Hp are degraded, and heme is transported out of endosomes by heme-responsive gene 1 protein (HRG1) [23,24]. Cytosolic heme stimulates the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by releasing Nrf2 from a cytosolic Nrf2-inactivating Kelch-like ECH-associated protein 1/Cullen 3/Rbx1/E3 ubiquitin ligase system (Keap1/Cul3/Rbx1/E3 complex) that prevents Nrf2 from moving into the nucleus; free Nrf2 undergoes translocation to the nucleus where it forms complexes with small Maf transcription factors that bind to the genomic antioxidant response element (ARE), activating the expression of phase 2 and antioxidant

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enzymes [25–27], including heme oxygenase-1 (HO-1) [28–34]. HO-1 catalyzes the conversion of free heme to biliverdin, Feþ2, and CO in the cell cytosol, nucleus, mitochondria, and endoplasmic reticulum [28–31]. In another contribution to heme clearance, HO-1 upregulates the production of interleukin (IL)-10 (which upregulates the expression of the CD163 surface receptor that internalizes heme-containing Hb) [24]. In physiologic concentrations (1–10 mM), Coþ2 from either CoCl2 or cobalt protoporphyrin upregulates the expression of HO-1, stimulating the catabolic detoxification of heme [34–38]. Additionally, Coþ2 (from CoCl2 [34,35,38–43] or cobalt protoporphyrin [44]) inhibits the activity of 5-aminolevulinic acid synthase (5-ALA synthase), inhibiting the synthesis of heme [34,35] in vivo [38–40,42,43] and in vitro [34,35,41] and diverting 5-ALA synthase into the synthesis of cobalt protoporphyrin in vivo, with the substitution of Coþ2 for Feþ2 [34, 35,38–45]. Cobalt and systemic antioxidant defenses Cobalt stimulates antioxidant defenses [34–60]. In physiologic concentrations (1–10 mM), Coþ2 from either CoCl2 or cobalt protoporphyrin upregulates the expression of HO-1 [34–38]. More than 85% of endogenously produced CO is produced by HO-1 degradation of heme [46], a process that is stimulated by Coþ2 ions [34–38] and that produces CO in physiologically active concentrations [47,48] that remain orders of magnitude below those that increase the plasma concentration of hypoxemic carboxyhemoglobin (and therefore are not cytotoxic) [49]. In these concentrations, CO produced enzymatically from heme by HO-1 stimulates the expression and activities of both mitochondrial superoxide dismutase (MnSOD) and extracellular SOD (EcSOD), increasing MnSOD-catalyzed conversion of superoxide produced during mitochondrial electron transfer chain reactions to hydrogen peroxide (which is degraded to water and oxygen by catalase) [26], and EcSOD-induced endothelial nitric oxide synthase activity, increasing the local formation of nitric oxide (NO) and ameliorating oxidative endothelial dysfunction [50]. Additionally, endogenously produced CO also activates Nrf2 by releasing Nrf2 from cytosolic Keap1/Cul3/Rbx1/E3 complexes that prevent Nrf2 from moving into the nucleus; free Nrf2 undergoes translocation to the nucleus where it forms complexes with small Maf transcription factors that bind to ARE, activating the expression of phase 2 and antioxidant enzymes [25–27]. Heme-derived CO also upregulates the expression of HO-1 in a positive feed-forward cycle [32,33]; the combined release of Nrf2 from Nrf2/Keap1/ Cul3/Rbx1/E3 complexes in the cytosol along with the release of brain acyl-coenzyme A hydrolase-1 (Bach1) from Bach1/Maf complexes bound to the nuclear Maf protein recognition element (MARE; that prevent the transcription of the gene encoding the HO-1 protein) allow free Nrf2 to translocate to the nucleus, bind to Maf proteins remaining bound to MARE, and initiate HO-1 gene expression [51–53]. More directly, CO produced enzymatically from heme by HO-1 inhibits the generation of reactive oxygen species (ROS) by NADPH oxidase [54–56] and HO-1 itself inhibits the production of ROS and decreases local oxidative stress [57]. Degradation of heme by HO-1 also produces biliverdin [28–31]. Biliverdin is converted rapidly to bilirubin by biliverdin reductase (biliverdin þ NADPH þ Hþ / bilirubin þ NADPþ) [30]. Bilirubin is exported out of the cell into the circulation, where it binds to albumin [46]. Albumin-bound bilirubin travels to the liver, where it dissociates from albumin and diffuses into hepatocytes,

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where bilirubin:uridine diphosphate glucuronosyltransferase produces water-soluble bilirubin monoglucuronide and bilirubin diglucuronide, which are excreted through the bile [46]. Free bilirubin is an antioxidant that reacts spontaneously with an oxidized reactant (such as hydrogen peroxide) to produce a reduced (detoxified) reactant and biliverdin, which biliverdin reductase (BVR) recycles to bilirubin in a cycle that amplifies the antioxidant potencies of both bilirubin and HO-1 and prevents depletion of glutathione (GSH) [46,58,59]. In addition to catalyzing the conversion of biliverdin to bilirubin, BVR forms a complex with dual specificity mitogen-activated protein kinase 1 and mitogen-activated protein kinase 3 (ERK1), which translocates to the nucleus where it reacts to phosphorylate, activate, and release ERK1-p [60]. ERK1-p activates cyclic AMP-dependent transcription factor-2 (ATF2), which activates cyclic AMP-responsive element-binding protein, which activates signal transducer and activator of transcription 1 a/b and the mini-chromosome maintenance protein complex (synchronizes the initiation of DNA replication and DNA elongation [61]), which together upregulate the expression of Nrf2, itself an inducer of the expression of endogenous antioxidants (e.g., SOD, NADPH:qionine oxidoreductase-1 [NQ01], thioredoxin reductase, sulfiredoxin, glutathione reductase, glutathione peroxidase, GSH, glutaredoxin, and peroxiredoxin) [60]. Through these mechanisms, BVR supports cell survival and resistance to prooxidant molecules [60]. Cobalt and inflammation Cobalt suppresses inflammation and supports antiinflammatory processes [34–38,47–50,61–95]. In physiologic concentrations (1–10 mM), Coþ2 from either CoCl2 or cobalt protoporphyrin upregulates the expression of HO-1 [34–38]. Increased HO-1 activity stimulates the production of physiologically active concentrations of CO from heme [47,48]. In these concentrations, heme-derived CO exhibits a number of antiinflammatory properties, including attenuation of the mitogen-induced activation of the early growth response-1 nuclear transcription factor, which stimulates inflammation [61–63]; activation of mitogen-activated protein kinase-1, reducing the activation of mitogen-activated protein kinase-8 (JNK-1) and mitogen-activated protein kinase-9 (JNK-2), decreasing JNK-1/2-induced secretion of proinflammatory IL-6, IL-18, tumor necrosis factor (TNF)-a, and IL-1 b, and attenuating cytokine-induced inflammation [49,50,62,64–69]; attenuation of heme-induced inflammatory injury caused by intracerebral hemorrhage [70]; attenuation of antigen-specific hyperinflammation [71]; and inhibition of TNF-a–induced cellular apoptosis of healthy cells [72,73]. In macrophages, physiologic concentrations of CO contribute to the resolution of inflammation through stimulation of the expression, synthesis, and activity of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that inactivates pro-inflammatory prostaglandins [74,75] and 15-lipoxygenase (15-LOX), an enzyme that catalyzes the synthesis of antiinflammatory lipoxin A4 (LXA4) [76,77]. Concurrent CO-induced activation of 15-PGDH and 15-LOX reduces polymorphonuclear (neutrophil)-mediated tissue damage, pain signals, unrestrained angiogenic endothelial cell proliferation, generation of ROS, neutrophil adhesion to endothelial cells, production of proinflammatory TNF-a and IL-12, and dendritic cell activation of T lymphocytes [77]. Additionally, 15-PGDH and 15-LOX together downregulate the synthesis and activity of proinflammatory thromboxane B2, increase the phagocytosis of tissue debris, and stimulate the production of a number of

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antiinflammatory factors, including IL-10; resolvin D1 (RvD1), which reduces expression of adhesion receptors by neutrophils and endothelial cells, generation of ROS, production of pro-inflammatory TNF-a, IL-12, and prostaglandin E2, transmigration of neutrophils, inappropriate neovascularization, and the expression of proinflammatory cytokines by microglial cells; resolvin D2 (RvD2), which reduces neutrophil adhesion to endothelial cells and stimulates endothelial cell production of antiinflammatory NO and prostacyclins and promotes microbial killing and the clearance of dead microbes; resolvin E1 (RvE1), which reduces phosphorylation signals, the activation of proinflammatory nuclear factor-kB (NF-kB), dendritic cell migration and production of IL-12, and neutrophil chemotaxis, and increases microbial killing and phagocytosis by neutrophils, detachment of microbe-containing neutrophils from sites of inflammation, clearance of microbe-containing neutrophils from the circulation, and the production of antiinflammatory LXA4; and protectin D1, which reduces the activation of proinflammatory NF-kB, the expression of proinflammatory cyclooxygenase-2, conversion of uncommitted Mf macrophages into M1 proinflammatory macrophages, the secretion of proinflammatory TNF-a and interferon-g, the migration of T lymphocytes to sites of inflammation, and renal fibrogenesis, increases neuroprotection, and protects retinal pigment epithelial cells from inflammation and oxidative damage [77]. Heme-derived CO attenuates oxidative stress-induced recruitment of toll-like receptor-4 (TLR4) to plasma membranes, decreasing both the interaction of the myeloid differentiation factor-2 domain of TLR4 with extracellular ligands and the endocytosis of TLR4, thereby inhibiting the initiation of proinflammatory downstream signaling cascades [78–82]. Heme-derived CO also attenuates the production and release of the proinflammatory high-mobility group box-1 (HMGB1) ligand for TLR4 [69], thereby inhibiting the generation of reactive oxygen species, the activation of NF-kB, the secretion of proinflammatory cytokines by pancreatic islet cells (reducing the risk for developing acute pancreatitis), vascular inflammation, susceptibility to cardiovascular disease, intraocular inflammation, intestinal inflammation, inflammatory bowel diseases, susceptibility to human cancers, pulmonary diseases, retinopathy, uveitis, and muscle fatigue [83–95]. Safety of dietary cobalt A number of investigators and expert panels have confirmed the safety of human dietary supplementation with Coþ2 [1,3,4,16, 19–22,96–99]. It has been demonstrated that Coþ2 ions are nonmutagenic in Ames tests, mouse lymphoma Tk mutation tests, Hprt mutation studies, and in vitro chromosomal aberration tests. Coþ2 ions exhibit no in vivo bone marrow toxicity; and do not produce bone marrow or spermatogonial chromosomal aberrations in vivo [97]. Although the International Agency for Research on Cancer of the World Health Organization concluded in 1991 that “cobalt and cobalt compounds are possibly carcinogenic,” based on extreme intakes in animal experiments, there was no evidence of human carcinogenicity of cobalt and cobalt compounds [4]. The US Agency for Toxic Substances and Disease Registry concluded in 2004 that the long-term minimal risk level (MRL) for oral Coþ2 for adults is 10 mg/kg of body weight daily (“An MRL is an estimate of the daily human exposure to a [potentially] hazardous substance that is likely to be without appreciable risk of adverse non-cancer health effects over a specified duration of exposure” [98]). The UK Expert Group on Vitamins and Minerals

concluded that 23 mg/kg of Coþ2 consumed daily “would not be expected to result in any adverse effects [AEs]” [1]. A group of reviewers concluded that a daily intake of 30 mg/kg of Coþ2 “would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Coþ2” without causing adverse health effects [99]. The US Institute of Medicine Food and Nutrition Board has concluded that no amount of ingested Coþ2 is associated with AEs [3]. The safety of human dietary supplementation with Coþ2 has been tested [16,20–22]. In one test, after 90 d of daily dietary supplementation with 1000 mg of Coþ2 (as CoCl2), no effects were seen in the participants on red blood cell (RBC) count; total white blood cell (WBC) count; hematocrit; plasma concentrations of Hb, total protein, albumin, total iron, ferritin, creatinine, creatine kinase, glucose, total cholesterol (TC), high-density lipoprotein (HDL)-associated cholesterol, total triacylglycerols (TGs), thyroid-stimulating hormone (TSH), total thyroxine (TT); plasma activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT); hearing sensitivities; retinal nerve dimensions; optical nerve dimensions; visual field index; spinal reflexes; left ventricular inner dimensions, wall thickness, and left ventricular ejection fraction (LVEF); right ventricular inner dimensions; intraventricular septum thickness; or left atrium volume [20]. During these 90 d of daily dietary supplementation with 1000 mg of Coþ2, no AEs were experienced [20]. In another experiment, after 90 d of daily dietary supplementation with 1000 mg of Coþ2 (as CoCl2), participants did not exhibit effects on RBC count; total WBC count; mean corpuscular volume; hematocrit; plasma concentrations of Hb, total protein, albumin, creatinine, creatine kinase, glucose, TC, HDL-associated cholesterol, total TGs, TSH, TT; plasma activities of AST and ALT; hearing sensitivities; LVEF; retinal nerve dimensions; or spinal reflexes [22]. However, the plasma concentrations of total iron and ferritin were decreased. No AEs were experienced by participants during the 90 d of daily dietary supplementation with 1000 mg of Coþ2 (as CoCl2) [22]. When healthy men and women supplemented their diets with 1000 mg/d of Coþ2 (as CoCl2) for 31 d, they experienced no polycythemia; thyroid dysfunction; immunologic sensitization to Coþ2; changes in clinical chemistry; or AEs of the kidneys, liver, or heart [21]. During 15 d of dietary supplementation with 400 mg/d of Coþ2 (as CoCl2), men experienced no AEs [19], and during 1 y of daily dietary supplementation with 1000 mg of Coþ2 (as CoCl2), no AEs were experienced by any of the participants [16]. Cobalt-stimulated endogenous enzymatic production of CO from heme is safe [34–41,49–53]. More than 85% of endogenously produced CO is produced by HO-1 degradation of heme [49], a process that is stimulated by Coþ2 ions [34–41] and that produces CO in amounts that generate physiologically active concentrations [50,51] that remain orders of magnitude below those that increase the plasma concentration of hypoxemic carboxyhemoglobin (and, therefore, are not cytotoxic) [52].

Conclusions The human health-supporting properties of dietary cobalt are underappreciated. When Coþ2 ions are consumed in amounts greater than provided as vitamin B12, systemic antioxidant and antiinflammatory processes are stimulated. Although Coþ2 ions act through the stimulation of HO-1 degradation of heme into biliverdin and CO, the endogenous enzymatic production of CO from heme is safe.

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