REVIEW PAPER Role of Mercury Toxicity in Hypertension, Cardiovascular Disease, and Stroke Mark C. Houston, MD, MS1,2,3 From the Department of Medicine, Vanderbilt University School of Medicine;1 Hypertension Institute and Vascular Biology;2 and the Division of Human Nutrition, Saint Thomas Medical Group, Saint Thomas Hospital,3 Nashville, TN Mercury has a high affinity for sulfhydryl groups, inactivat- arrhythmias, reduced heart rate variability, increased caro- ing numerous enzymatic reactions, amino acids, and tid intima-media thickness and carotid artery obstruction, sulfur-containing antioxidants (N-acetyl-L-cysteine, alpha- cerebrovascular accident, generalized atherosclerosis, and lipoic acid, L-glutathione), with subsequent decreased oxi- renal dysfunction, insufficiency, and proteinuria. Pathologi- dant defense and increased oxidative stress. Mercury cal, biochemical, and functional medicine correlations are binds to metallothionein and substitute for zinc, copper, significant and logical. Mercury diminishes the protective and other trace metals, reducing the effectiveness of met- effect of fish and omega-3 fatty acids. Mercury inactivates alloenzymes. Mercury induces mitochondrial dysfunction catecholaminei-0-methyl transferase, which increases with reduction in adenosine triphosphate, depletion of glu- serum and urinary epinephrine, norepinephrine, and dopa- tathione, and increased lipid peroxidation. Increased oxi- mine. This effect will increase blood pressure and may be dative stress and reduced oxidative defense are common. a clinical clue to mercury-induced heavy metal toxicity. Selenium and fish containing omega-3 fatty acids antago- Mercury toxicity should be evaluated in any patient with nize mercury toxicity. The overall vascular effects of mer- hypertension, coronary heart disease, cerebral vascular cury include increased oxidative stress and inflammation, disease, cerebrovascular accident, or other vascular reduced oxidative defense, thrombosis, vascular smooth disease. Specific testing for acute and chronic toxicity and muscle dysfunction, endothelial dysfunction, dyslipidemia, total body burden using hair, toenail, urine, and serum and immune and mitochondrial dysfunction. The clinical should be performed. J Clin Hypertens (Greenwich). consequences of mercury toxicity include hypertension, 2011;13:621–627. Ó2011 Wiley Periodicals, Inc. coronary heart disease, myocardial infarction, cardiac There is increasing concern regarding the overall health found in human tissue after conversion from the other effects of chronic exposure to various heavy metals in forms. Organic mercury in the form of methyl and the environment. This is particularly true of mercury ethyl mercury is primarily from fish, sea mammals, and less so with other heavy metals such as cadmium, and thimerosal vaccines. Although dental amalgams lead, aluminum, iron, and arsenic. The cardiovascular have historically been the major source of human consequences of mercury toxicity have not been exposure, fish and sea mammals are becoming an carefully evaluated until recently. This paper will criti- increasing environment source of potential mercury cally review the cardiovascular consequences of mercury toxicity.1,2,4,5 toxicity in humans as it relates to hypertension, general- ized atherosclerosis, coronary heart disease (CHD), MERCURY BIOTRANSFORMATION myocardial infarction (MI), cardiac arrhythmias, heart AND BIOMETHYLATION rate variability, sudden death, cerebrovascular accidents Mercury from various sources, including elemental (CVA), carotid artery disease, renal dysfunction, and mercury from earth sources or inhaled mercury vapor, total mortality. methyl and ethyl mercury are converted by biomethy- lation to inorganic divalent mercury, the toxic form in TYPES OF MERCURY human organs and tissues (Figure 1).4 Divalent Mercury exists in three basic forms: elemental, inor- mercury is soluble and stable in water and undergoes ganic, and organic (Table I).1–5 Dental amalgams are biomethylation to methyl mercury, which is found in the most common source for elemental mercury vapor, high concentrations in certain fish and sea mammals. which is a stable monoatomic gas. Inorganic mercury, It is this source that is becoming the major source of which is a divalent compound, is the toxic species human exposure to mercury. The Environmental Protection Agency has determined 4 Address for correspondence: Mark Houston, MD, Hypertension the safe daily intake of mercury to be <0.1 lg ⁄ kg ⁄ d. Institute, 4230 Harding Road, Suite 400, Saint Thomas Medical Plaza, However, 12% of women have hair mercury above the Nashville, TN 37205 E-mail: [email protected] level at which stopping consumption of highly contami- nated fish would be advisable (1.0 lg ⁄ g).4 It is estimated Manuscript received January 15, 2011; Revised: April 21, 2011; Accepted: May 13, 2011 that one dental amalgam filling releases about 3 lgto DOI: 10.1111/j.1751-7176.2011.00489.x 17 lg of mercury vapor per day. The typical amalgam is Official Journal of the American Society of Hypertension, Inc. The Journal of Clinical Hypertension Vol 13 | No 8 | August 2011 621 Role of Mercury Toxicity in Hypertension | Houston TABLE I. Mercury Types Hg 1. Elemental Mercury vapor (Hg°), Dental amalgams a stable monoatomic gas 2. Inorganic Divalent mercury (Hg2+) Toxic species in human Ubiquinone-cytochrome B region and NADH dehydrogenase and 2+ + tissue after conversion Fe and Cu ions A3Cub Center Cytochrome C + 3. Organic Methyl mercury (CH3Hg ) Fish, sea mammals + Ethyl mercury (CH3CH3Hg ) Thimersol vaccines Depolarization Inner Mitochondrial Membrane Autoxidation Inner Mitochondrial Membrane Peroxidation Inner Mitochondrial Membrane divalent mercury + 2+ Methyl mercury (CH3Hg ) Hg + Ethyl mercury (CH3CH3Hg ) converts toxic species Altered Calcium H2O2 Deletes Mito TBARS Oxidation Homeostasis GSH (> 50%) Lipid of Peroxidation Pyridine > 70% Nucleotide NAD(p)H Mercuric Salt Mercurous Salt Soluble in H2O Increased Oxidant Stress Decreased Oxidant Defense Diphenyl-Hg Biomethylation Phenyl-Hg FIGURE 2. Pathophysiologic basis of mercury toxicity, mitochondrial dysfunction, and oxidative stress. + Methyl Mercury CH3Hg Hg2+ antioxidant and protects against oxidative stress, 3,4,5,8,9,12 Fish inflammation, and cardiovascular disease. This mercury-induced reduction in oxidant defense and increase in oxidative stress increase the risk for FIGURE 1. Mercury biotransformation and biomethylation. CVD and CVA. Selenium antagonizes some of the adverse effects of mercury by forming a seleno-mer- cury complex in tissue that is less toxic.9,14–20 Higher composed of 50% mercury, 25% silver, and 25% tin, intake of selenium reduces mercury-related CVD and copper, and nickel.4,6,7 Fish and sea mammals provide CVA. about 2 lg ⁄ dto3lg ⁄ d depending on the type and amount consumed.1,2,4,5 The long-lived large predatory PHYSIOLOGIC BASIS OF MERCURY fish such as swordfish, tilefish, shark, and king mackerel TOXICITY contain about 1 lg of methyl mercury per gram. Pike, Mercury induces mitochondrial dysfunction and oxida- whale, bass, tuna, and trout are about 0.1 lg to 0.5 lg tive stress.21,22 The primary mitochondrial dysfunction of mercury per gram. Nine vaccines that contain thimer- occurs at the ubiquinone-cytochrome B region and osol (50% mercury) as a preservative would give an esti- with NADH dehydrogenase causing displacement of mated exposure of 62 lg of organic mercury.1,2,4,5 All Fe++ and Cu+ ions in the a3Cub center of cytochrome other sources of mercury provide about 0.3 lg ⁄ d.1,2,4,5 C (Figure 2). This results in depolarization and auto- oxidation of the inner mitochondrial membrane with IMPORTANT FACTS ABOUT MERCURY lipid peroxidation and severe mitochondrial dysfunc- Mercury is the most dangerous of all the heavy met- tion. Physiologic consequences include increased als.8 It will modify the distribution and retention of hydrogen peroxide, depletion of mitochondrial gluta- other heavy metals.9–11 Mercury has no known physi- thione by more than 50%, increased lipid peroxidation ologic role in human metabolism, and the human body markers such as TBARS by more than 70%, oxidation has no mechanisms to actively excrete mercury.12 of pyridine nucleotides such as NAD(p)H, and Mercury thus accumulates during life so that the aver- altered calcium homeostasis.21,22 This severe mito- age 165-lb person has a total body burden of about chondrial dysfunction increases oxidant stress and 13 mg of mercury.8 Mercury has a high affinity for reduces oxidant defenses, which has enormous health sulfhydryl groups, various enzymes and amino acids, implications. N-acetyl cysteine (NAC), alpha lipoic acid (ALA), and The primary three sources of mercury-induced lipid glutathione (GSH), which provide about 10% to 50% peroxidation include the Fenton reaction, affinity for of the plasma protein antioxidant capacity.8,12,13 Both sulfhydryl groups, and selenium deficiency.8 Mercury NAC and ALA, as well as cysteine, are precursors for serves as a direct catalyst in Fenton-type reactions and glutathione, which is the most potent intracellular as an indirect catalyst via iron stimulation, which 622 The Journal of Clinical Hypertension Vol 13 | No 8 | August 2011 Official Journal of the American Society of Hypertension, Inc. Role of Mercury Toxicity in Hypertension | Houston TABLE II. Vascular Biologic Effects of Mercury TABLE III. Summary of the Overall Vascular Biologic Effects of Mercury 1. Increased free radical production and increase in oxidative stress