Interaction of mercury species with proteins: towards possible mechanism of mercurial toxicology

Sharmin Akther Rupa; Md Abdul Majed Patwary; Mohammed Mahbubul Matin; William Emmanuel Ghann; Jamal Uddin; Mohsin Kazi

doi:10.1093/toxres/tfad039

. 2023 May 30;12(3):355–368. doi: 10.1093/toxres/tfad039

Interaction of mercury species with proteins: towards possible mechanism of mercurial toxicology

Sharmin Akther Rupa ¹, Md Abdul Majed Patwary ^2,^✉, Mohammed Mahbubul Matin ³, William Emmanuel Ghann ⁴, Jamal Uddin ⁵, Mohsin Kazi ⁶

PMCID: PMC10311172 PMID: 37397928

Abstract

The nature of the binding of mercurials (organic and inorganic) and their subsequent transformations in biological systems is a matter of great debate as several different hypotheses have been proposed and none of them has been conclusively proven to explain the characteristics of Hg binding with the proteins. Thus, the chemical nature of Hg-protein binding through the possible transportation mechanism in living tissues is critically reviewed herein. Emphasis is given to the process of transportation, and binding of Hg species with selenol-containing biomolecules that are appealing for toxicological studies as well as the advancement of environmental and biological research.

Keywords: mercury, methylmercury, toxicology, selenium, protein

Graphical Abstract

Introduction

Mercury (Hg) is a naturally occurring global contaminant^1–4 that is released into the biosphere by both natural processes and anthropogenic activities.⁵^,⁶ Hg exists in several forms: elemental mercury vapor Hg0, inorganic divalent Hg²⁺, and organomercury compounds, such as monomethyl mercury (MeHg; CH₃Hg⁺)⁷^,⁸ and dimethylmercury [(CH₃)₂Hg].⁹^,¹⁰ Both inorganic and organic forms of Hg are toxic because of their high affinities to thiol-containing proteins and enzymes (Fig. 1).¹¹ Hg²⁺ is highly nephrotoxic³^,^12–14 as it primarily accumulates in the kidney more than in any other organ of the body.¹²^,¹⁴ Hg0 in gaseous form can be rapidly oxidized to Hg²⁺ in the blood and can damage the body through chemical alterations in the tertiary and quaternary structures of proteins; it can diffuse through the blood–brain barrier (BBB) and become a neurotoxin.³^,¹⁵^,¹⁶ Hg²⁺ can also interact in vivo with lipid bilayer membranes (e.g. phosphatidylethanolamine (PE), phosphatidylserine (PS), and human erythrocyte membranes) because of its high affinity to the charged head group of lipids.^17–19 Although Hg²⁺ forms very stronger complexes with thiolate ligands with stability constants ranging from 10²⁶ to 10⁵³, it can also bind to different other functional groups such as carboxylates, halides, hydroxides, and amines, with affinities at least 10 orders of magnitude lower.^20–22

Fig. 1 — Possible binding pathway of the Hg²⁺ and CH₃Hg⁺ with proteins.

One of the simplest and most detrimental species involved in the biogeochemical Hg cycle is CH₃Hg⁺.²^,²³ CH₃Hg⁺ is a potent neurotoxin produced from Hg²⁺ that is bioavailable to animals, including humans.²^,²⁴^,²⁵ Evidence also exists that CH₃Hg⁺ may be linked to a variety of cardiovascular¹^,²⁶ and reproductive²⁷ effects in mammals, including humans. It can cross the BBB by LAT 1 and 2 as a L-cysteine complex¹⁵^,^28–30 and cause disturbances in several cellular processes, including synaptic function, oxidative stress, ionic homeostasis, synthesis of homeostasis and selenoprotein synthesis³¹, and induce selenium (Se) deficiency.³² Homo-cysteine may also deliver CH₃Hg⁺ to the BBB.³⁰ (CH₃)₂Hg is highly toxic as 4 mg/L in the bloodstream can cause death.¹⁰ Notably, both Hg²⁺ and CH₃Hg⁺ are soft Lewis’s acids, and therefore, have an extremely high affinity for thiol groups (-SH). In the presence of free thiols, CH₃Hg⁺ complexes are kinetically labile and experience rapid ligand exchange although they have a very high thermodynamic complex formation constant of 10¹⁵⁻10³⁰ with thiols.³^,³³ The strong interactions of Hg²⁺ and CH₃Hg⁺ ions with thiol and selenol groups dictate that these thiol- and selenol-containing biomolecules are the primary sites of the aforementioned Hg-species in biological systems.³⁴

Thus, understanding the interaction of Hg-species with proteins is of practical as well as fundamental importance.²⁴ Therefore, the mechanisms of toxicity of Hg-species which include their interaction between Se and Hg³^,^35–42 and the underlying Hg–protein interactions require immediate attention. Here, we report a critical review of possible toxicity mechanisms that are associated with Hg-protein interactions within organs with a focus on molecular toxicology.

Toxicity owing to Hg²⁺/CH₃Hg⁺

Human exposure to Hg-species can cause several types of health issues, with the magnitude being determined by the exposure dose, route of exposure, chemical specie, age, and gender. Acute toxicity which is caused by the spillage of liquid Hg in restricted spaces or in hot areas can lead to paroxysmal cough, chills, chest pain, nausea, pulmonary infiltration, and vomiting.⁴³^,⁴⁴ Chronic toxicities usually result from prolonged human exposure to Hg0, which can be metabolized into Hg²⁺.⁴⁴ Symptoms and signs of serious poisoning from inhaled Hg0 are tremors, gingivitis⁴⁴ and may also cause erethism, which is a constellation of neuropsychiatric results that includes anorexia, depression, excessive timidity, insomnia, emotional instability, memory loss, shyness, uncontrolled perspiration, vasomotor disturbance, and blushing.⁴⁴ Severe kidney damage was reported from inhaled Hg0, but such terrible circumstances are infrequent and only originate with chronic exposures to Hg0, typically of 500 μg Hg/m³ in the air.⁴⁵

Workers examined after 20–35 years of elemental mercury exposure, had peak urine concentrations of above 600 μg/L Hg, and suffered from drastically decreased strength, decreased coordination, increased tremors, and decreased sensation.⁴⁵^,⁴⁶ Urinary total Hg concentrations >800 μg/L can lead to death.⁴⁴ The Environmental Protection Agency has established the secure daily consumption of Hg to be <0.1 μg/kg/d.⁴⁷ According to the WHO, 10–15% of oral consumption of HgCl₂ is absorbed from the gastrointestinal (GI) tract in adults into the bloodstream and excreted via urine and feces at a roughly equal rate.⁴⁸^,⁴⁹ GI absorption may be higher in children. Experiments with rats indicated that GI absorption was as high as 38% in neonatal rats provided an oral dose of HgCl₂ compared to absorption values of below 1% in adult rats on a standard diet.⁵⁰^,⁵¹ Chronic exposure to Hg²⁺ primarily affects the renal cortex and may cause renal failure (dysuria, hematuria, oliguria, proteinuria, and uremia) or GI problems (colitis, stomatitis, gingivitis, extreme salivation).⁵² Exposure to Hg²⁺ also results in an increased risk of cardiovascular disease, and deep cardiotoxicity with hypertension, myocardial infarction, coronary heart disease, enhanced carotid intima-media thickness, carotid obstruction, cerebrovascular accidents, prevalent atherosclerosis, and total surge in cardiovascular mortality.⁴⁷^,⁴⁸^,⁵³^,⁵⁴ Rossoni et al.⁵⁵ showed that injecting rats with HgCl₂ of 5 mg/kg resulted in cardiac diastolic collapse and pulmonary hypertension. Another study on rats demonstrated that severe exposure to 680 ng/kg of HgCl₂ result in an enhanced heart rate, blood pressure, and vascular reactivity to phenylephrine.⁵⁶ Prior investigations using 265 female and 6784 male workers from a mercury mine sand mills reported that long-term exposure to Hg²⁺ increases the risk of cardiovascular mortality.⁴⁸^,⁵³

Exposure to CH₃Hg⁺ may cause autonomic dysfunction, nervous demyelination, sensory nerve conduction delay, irregular neuronal migration, and irregular central nervous system (CNS) cell division. Additionally, prolonged exposure causes paresthesia, cerebellar ataxia, peripheral neuropathy, spasticity, akathisia, dementia, loss of memory, constrained vision, dysarthria, tremors, and depression.⁵² There were two major poisoning incidents associated with CH₃Hg⁺ exposure in Japan³^,²³^,⁵⁷ and in Iraq, which occurred between the 1950s and the early 1970s.³^,⁵⁸ Poisoning in Minamata/Japan arose due to acute exposure via the consumption of CH₃Hg⁺ contaminated fish with a daily intake of 3–7 μg/kg.⁵⁹ Evidence has shown that patients who died from the disease had high levels of Hg in the brain (2.6–24.8 mg/L), the liver (22–70.5 mg/L), and the kidneys (21.2–140 mg/L).²³ Moreover, there have been several suggestions that the Minamata tragedy might have been due to mercury species other than CH₃Hg⁺, which is still being debated.⁶⁰^,⁶¹ Subsequently, in Iraq, human poisoning was the consequence of the intake of homemade bread, made from grain treated with CH₃Hg⁺ and CH₃CH₂Hg⁺ compounds.²⁶ Later the fungicide ethyl mercury-p-toluene sulfonanilide was claimed to be responsible for two outbreaks in Iraq in 1956 and 1960.⁵⁸ The total amount of Hg accumulated in the blood of each person was determined by the amount of homemade bread consumed per day, the number of days the contaminated bread was consumed, and the CH₃Hg⁺ concentration in the bread. For the consumption of 1 mg of Hg, the Hg concentration in the blood of younger patients (aged 10–15 years) was 17 and 9 μg/L for the older set (aged above 18 years).⁵⁸ CH₃Hg⁺ is absorbed almost completely from the GI tract and excreted predominantly via the feces.⁴⁹

Interaction of Hg²⁺ and CH₃Hg⁺ with proteins

Many biochemical reactions that support life are catalyzed by the action of enzymes. The binding of both organic and inorganic forms of mercury can cause conformational changes in these enzymes and block their activity. For example, Hg²⁺ exposure causes dysfunction of several biological enzymes such as paraoxonase, glutathione peroxidase (GPx), and alkaline phosphatase in humans.⁴⁷ Glutathione (γ -glutamyl-cysteinyl-glycine, GSH) is the most abundant cellular “free” thiol in animal tissues, plants, and microorganisms. Hg (SG)₂ is the dominant complex between Hg²⁺ and GSH under physiological pH.⁶² Alteration of the function of these complexes and highly structured biochemical systems may describe several negative indications of Hg poisoning,⁶^,⁷^,⁶³^,⁶⁴ which are described in detail below.

Interaction of Hg²⁺ and CH₃Hg⁺ with erythrocytes

Red blood cells (RBCs) are undeniably a substantial site of Hg toxicity since both Hg²⁺ and CH₃Hg⁺ favorably accumulate in these cells and play an important role in delivering mercury species to target organs.^65–67 A schematic representation of Hg²⁺ and CH₃Hg⁺ toxicity subsequent to oxidative stress conditions in human erythrocytes is shown in Figure 2. Hg²⁺ ions are mostly absorbed in the GI tract and then flow into the blood where they interact with erythrocytes and produce reactive oxygen species (ROS), reactive nitrogen species (RNS), and free radicals.⁶⁸ These species can oxidize hemoglobin (Hb) to methemoglobinemia (MetHb), thereby reducing the O₂ carrying capability of Hb. Wierzbicki et al.⁶⁹ stated that exposure to Hg0 demonstrated a statistically substantial increase in blood coagulation. Furthermore, long exposure of human red blood cells to a low concentration of Hg²⁺ of 0.25–5 μM for 1–48 h resulted in erythrocyte shape variations from discocytes to echinocytes to spherocytes, supplemented by microvesicle (MV) production.⁷⁰ It was confirmed by ex vivo and in vivo rat thrombosis models, where Hg²⁺ medication of 0.5–2.5 mg/kg boosted phosphatidylserine (PS) exposure, which could develop thrombin production and adhesion to vascular endothelial cells and is considered a direct sign of procoagulant activation.⁷⁰ Investigations in rats exposed to a non-nephrotoxic dose of CH₃Hg⁺ indicated that approximately 30% of the administered dose is identified in blood after 24 h and 99% of CH₃Hg⁺ in the blood is in erythrocytes.⁷¹

Fig. 2 — Schematic depiction of HgCl₂ and CH₃Hg⁺ toxicity resulting from oxidative stress in human erythrocytes. Mercurial ions can react with GSH and proteins in the erythrocytes leading to the production of ROS and RNS. These reactive species oxidize Hb to MetHb thus shrinking the oxygen-carrying ability of Hb.

Possible mechanism of Hg²⁺ poisoning in erythrocytes

Hg²⁺ can cross the cell membranes of erythrocytes by using different transporters. In vivo analyses in ligated bile ducts of rats indicated the fecal excretion of Hg²⁺ is owing to the secretory-like movement of Hg²⁺ from the blood into the intestinal lumen.⁷² These data suggest that amino acid transporters, multidrug resistance-associated proteins (MRPs), and/ or organic anion transporters OATs are likely involved in the transport of Hg^2+.⁷³ Ganapathy and co-workers reported that amino acid and/or peptide-based transporters, which are prevalent in erythrocytes, may be used to pass thiol S-conjugates of Hg²⁺ into enterocytes.⁷⁴ Studies have shown that divalent metal transporter 1 such as DMT1; SLC11A2 is in the apical membrane of enterocytes, so it is possible that Hg²⁺ is taken up into erythrocytes by DMT1.⁷⁵ In vivo studies in mice indicate the function of DMT1 in the intestinal uptake of Hg^2+.⁷⁶

In the cytosol, Hg²⁺ reacts with GSH and Hb to form the ternary mixed-ligand complex GSH-Hg²⁺-Hb in solution, which was proven by ¹H NMR.⁷⁷^,⁷⁸ Weed and coworkers⁷⁹ concluded that the projected underlying mechanism of HgCl₂ toxicity is associated with the higher affinity of Hg²⁺ for sulfhydryl groups of Hb that can alter its structural function. Further investigations showed that Hb binds 90% of the absorbed HgCl₂ and stromal protein accounts for a maximum of 5%.⁷⁹ Moreover, the treatment of erythrocytes with diverse concentrations of HgCl₂ (1–100 μM) resulting the oxidation of Fe²⁺ of Hb to Fe³⁺ form providing methemoglobin that does not act as an O₂ transporter.⁶⁵ Hb oxidation was due to heme degradation and the production of free iron.⁷⁹ Protein oxidation was significantly increased with a concurrent reduction in free amino and sulfhydryl groups as well as GSH content.⁶⁶ This was established when H₂O₂, peroxynitrite, superoxide anion, and HNO₃ production were obtained to be dose-dependently boosted in HgCl₂-treated erythrocytes.⁸⁰^,⁸¹

Possible mechanism of CH₃Hg⁺ poisoning in erythrocytes

A possible mechanism of CH₃Hg⁺ poisoning could be the reversible binding to the -SH group of the erythrocyte membrane,⁸² which can adversely damage their permeability and rigidity. Investigations with human erythrocytes indeed showed that the Na⁺ and K⁺-ATPase were proficient in binding seven molecules of CH₃Hg⁺ while the Mg⁺ and Ca²⁺-ATPase bound only one CH₃Hg⁺ molecule.⁸² Manifold transport techniques seem to be linked to the uptake of CH₃Hg⁺ into erythrocytes.⁸³ Interestingly, the binding of Hg²⁺ ions to the Na⁺ and K⁺-ATPase has been demonstrated to significantly inhibit this enzyme activity.⁷³ It has been hypothesized that the organic anion transporter system is engaged primarily or exclusively in the uptake of CH₃Hg⁺.⁸⁴^,⁸⁵ Within the cell, CH₃Hg⁺ binds to small molecules of human erythrocytes but it can also inhibit cytosolic enzymes (i.e. glutathione peroxidase (GPx) and thioredoxin reductase (TrxR)), metalloproteins, such as Hb^86–88 and GSH.⁸⁹^,⁹⁰

Interaction of Hg²⁺ and CH₃Hg⁺ with central nervous system proteins

CNS enzymes inhibited by Hg²⁺ are acid or alkaline phosphatase, α-mannosidase and succinic dehydrogenase,⁹¹ as well as neprilysin.⁹² CH₃Hg⁺ causes neurodegenerative diseases as it can increase the production of reactive free oxygen radicals (O₂^•−) within the CNS at 10 μM CH₃Hg⁺ treatment for 40 min.⁴⁵^,⁵⁹ An increase of these reactive oxygen free radicals exposes CNS enzymes to a certain degree of oxidative stress by preventing their function, which is the root cause of neurodegenerative diseases⁹³ such as Parkinson’s disease, amyotrophic lateral sclerosis, Alzheimer’s disease⁹⁴, and apoptotic cell death.⁹⁵ Within the CNS,²⁹ CH₃Hg⁺ combines covalently with sulfhydryl (thiol) groups from proteins and non-protein molecules, i.e. glutathione (GSH; γ-glutamyl-cysteinyl-glycine),⁹⁶ which led to a significant increase in mitochondrial ROS.⁹⁷^,⁹⁸ In vivo studies on pregnant mice showed that gestational exposure to CH₃Hg⁺ caused a dose-dependent inhibition of cerebral GSH levels by forming GS–HgCH₃ complex.⁹⁹ This data suggest that CH₃Hg⁺ disrupts the development of the GSH antioxidant system in CNS,¹⁰⁰ which consequently induces the production of ROS and oxidative destruction of biomolecules (lipids, nucleic acids, and proteins). CH₃Hg⁺ interrupts the mitochondrial electron transportation chain, which increases the growth of ROS, for instance, H₂O₂ and superoxide anion (O₂^•−), NO^•, and ONOO^−.⁹⁷^,¹⁰¹ In the brain, impacts on mitochondrial respiration have been published to occur at 10–100 μM CH₃Hg⁺, which causes inhibition of glycolysis and tricarboxylic acid cycle activity and reduces adenosine triphosphate consumption.⁵⁹ At a concentration of 0.5–1 μM,¹⁰² CH₃Hg⁺ disrupts cytoarchitecture and the construction of neurons as it strongly binds to the sulfhydryl group of tubulins, which inhibits the microtubule organization.⁶³^,⁹⁴ Intracellular signaling of muscarinic, nicotinic, and dopaminergic receptors are affected due to the binding of CH₃Hg⁺ to -SH groups, which also block the Ca²⁺ channels within the neuron.⁹⁴ At 50 μM, CH₃Hg⁺ blocks the Ca²⁺ channel whereas, at 100 μM, it rapidly blocks both Ca²⁺ and Na⁺ channels.⁹³ Chin-Chan et al.⁹² showed that the interaction of Hg²⁺ with neprilysin at 20 μM concentration reduces the activity of this enzyme.

Mechanism of Hg²⁺ and CH₃Hg⁺ − induced neurotoxicity

Although there has been a good deal of research on the toxic effect of the interaction of Hg²⁺ and CH₃Hg⁺ with several biological CNS enzymes, complete knowledge of the mechanisms causing this toxicity is not fully elucidated. The mechanism through which Hg²⁺ and CH₃Hg⁺ target specific enzymes and distort their structure is understood in limited detail. Also, very little knowledge about the transportation mechanism of Hg²⁺ and CH₃Hg⁺ from blood to the brain. Quite a few earlier studies have analyzed possible mechanisms for transport across the BBB of Hg²⁺ and CH₃Hg⁺, which is summarized in detail here:

Possible pathways of transportation of Hg²⁺ to CNS

There are many uncertainties about how inorganic Hg²⁺ is transported through the BBB. Inorganic Hg²⁺ has a much greater Lewis’s acidity than CH₃Hg⁺ and thus has an even better affinity to thiols.³ Hg²⁺ can form L-cysteine complexes with different stoichiometries, such as HgL, HgL₂, Hg₂L₂, and Hg₃L₂ (where L represents the cysteine ligand). Because of stability, two coordinated Hg(SCys)₂ is expected to form more rapidly.¹⁰³ Also within the CNS, Hg²⁺ is expected to bind the thiolates to form [Hg^II(SR)_n]^2–n (R = Cys, G, Hcy) complexes.¹⁰⁴

Surprisingly, due to the exceptional polarizing power of Hg²⁺, it passes the BBB less freely than CH₃Hg⁺. Nevertheless, in general, there is no evidence that Hg(SG)₂, Hg(SCys)₂, or inorganic Hg²⁺ can cross the BBB.³³ In the brain, inorganic Hg²⁺ is generated from the oxidation of Hg0 or demethylation of CH₃Hg⁺.¹⁰⁵ Hg0 is monoatomic gas with no charge and is lipid-soluble, it is highly diffusible across BBB. Approximately, 10% of the Hg0 in the blood could passes to the BBB.¹⁰⁶ Once in a cell, Hg0 undergoes rapid oxidation to inorganic Hg²⁺ by the catalase H₂O₂ pathway.⁴⁴ Nevertheless, the prospect of a different route to the brain has been suggested by Henriksson and Tjälve,¹⁰⁷ who proposed that since secondary neurons of the olfactory system are directly exposed to inhaled air, Hg0 might reach the brain through transport along the olfactory nerves. Later, Maas et al.¹⁰⁸ proved that there is no correlation between the transportation of Hg0 from dental amalgam fillings to the cranial cavity by a direct oronasal route. There is a possibility that Hg0 can cross cell membranes through a protein-lined transport channel. Although there is no evidence that thiol-holding biomolecules are associated with the transport, uptake, or excretion of Hg0.⁴⁴

Possible pathways of transportation of CH₃Hg⁺ to the CNS

After exposure to CH₃Hg⁺, the absorption of CH₃Hg⁺ in the GI tract is approximately 90–95% and CH₃Hg⁺ is then transported into the bloodstream.⁹⁴^,¹⁰⁹ Hammond et al. ¹¹⁰ proposed that CH₃Hg⁺ formed lipid-soluble compounds, and consequently could passively diffuse across the BBB. Goldmann first proved that there is a barrier separating the CNS from the blood.¹¹¹ This barrier is constructed of endothelial cells, which selectively pass essential nutrients while excluding non-essential substances. Solutes which can pass through the BBB, require a specific transport system.¹¹¹ It was observed that because of the extreme chemical affinity of the CH₃Hg⁺ to –SH groups, a cysteine complex (CH₃Hg-Cys) is formed¹⁰¹:

Higher coordination number complexes have also been reported, such as CH₃Hg(SCys)₂ and CH₃Hg(SCys)₃, involve the binding of two or three cysteine molecules to the methylmercury atom.¹¹²^,¹¹³ Multinuclear complexes, such as (CH₃Hg)₂SCys, involve the binding of two methylmercury atoms to a single cysteine molecule, with one mercury atom bonded to the sulfur site and the other to the carboxylic group.¹¹³ Due to more linear C–Hg–S bond (∼179⁰), CH₃Hg-Cys mimics the larger amino acid methionine.¹⁰⁹^,¹¹³ Thus L-cysteine facilitates the active transport of CH₃Hg⁺ across the capillary endothelial cell membrane via the LAT1 system (Fig. 3).^111–118 However, exposure of zebrafish larvae to 2 μM CH₃Hg⁺ L-cysteineate for 12 h resulted in the accumulation of analogous cellular levels of mercury in the eye lens.¹¹⁷ Although the mechanism of CH₃Hg⁺ transport into the lens epithelial cells is unknown, it is conceivable that CH₃Hg⁺ L-cysteineate is moved into lens epithelial cells on the large neutral amino acid carriers (system L or LAT).¹¹⁷

Fig. 3 — Possible transportation of CH₃Hg⁺ to the CNS via the BBB. Once in the brain, methylmercury can interact with various cellular components, including GSH, proteins, and enzymes, generating ROS that causes oxidative stress, mitochondrial dysfunction, and neuronal cell death.

The procedure is so refined that the L-optical enantiomorph is carried out at a higher rate.¹⁰⁹ The affinity of CH₃Hg⁺ for the anionic form of -SH groups is on the order of 10^15–23, whereas its affinity constants for carboxylate or amino groups containing ligands are about 10 orders of magnitude lower.³ Indeed, although other transporters have been published to mediate CH₃Hg⁺ transport, LAT1 appears to be the key, if not the only, transporter responsible for CH₃Hg⁺ transport from peripheral tissues to the CNS.²⁹ Because of the kinetic instability of CH₃Hg–SR bond (–SR = amino acids containing S), it also undergoes rapid exchange reaction with other –SH groups of proteins or enzymes that may occur within CNS that inactivate some proteins:

where, RSH and R^’SH denote two different thiols.

Thus, a third CNS pool must signify irreversibly bind CH₃Hg⁺ to high molecular weight –SH controlling ligands. The elimination of CH₃Hg⁺ from diffusible –SH enclosing ligands is obviously the most important mechanism for concentrating CH₃Hg⁺ within the CNS.¹⁵ As though there is some information about the transportation mechanism of CH₃Hg⁺, the amount and the form of transportation are unknown as well as are expected to be small since lower molecular weight thiol-holding ligands are existing only in trace amounts in the blood plasma.¹¹⁰ Also, the mechanism of CH₃Hg⁺ absorption into the GI tract remains elusive.

Interaction of Hg²⁺/CH₃Hg⁺ with vascular and cardiovascular proteins

Hg²⁺ and CH₃Hg⁺ have higher affinity to form complexes with thiol, nitrogen, and sulfur-containing ligands that selectively deactivate several key enzymatic proteins, amino acids, and sulfur-containing antioxidants within the vascular systems.¹¹⁹^,¹²⁰ These Hg-sulfhydryl interactions can inhibit ATP hydrolysis through direct inhibition of myosin-ATPase, Ca²⁺-ATPase, and Na⁺/K⁺-ATPase enzyme activity within vascular cells.¹¹⁹ Hg²⁺ has been noted to alter the structure and function of the endothelial vascular cells.^119–121 Several studies have demonstrated that Hg²⁺ selectively impairs the NO pathway via the alteration of expression of NO synthase (NOS) and improved superoxide anion (O₂^•−) growth from NADPH oxidase.⁹⁴^,¹²²

Vasoconstriction and vasorelaxation are supported by the bioavailability of NO.⁶³^,¹²⁰^,¹²³ The reduction in NO bioavailability and increased ROS production can lead to endothelial dysfunction, which is characterized by impaired endothelium-dependent vasorelaxation.¹²⁴ For example, an experiment on rats at a concentration of 10⁻⁶ M of HgCl₂ alters the structure and function of vascular endothelial cells¹²⁵ while other studies have demonstrated that rats chronically treated with 1.25 × 10⁻⁶ M/L of HgCl₂ in drinking water for 30 days reduced the bioavailability of NO and reduced the endothelium-dependent relaxant response.¹²³ Acute exposure to Hg²⁺ and CH₃Hg⁺ are related to an improved risk of cardiovascular disease and profound cardiotoxicity. Numerous studies have reported that the Hg²⁺ mediated cardiovascular disorders including coronary heart disease, carotid obstruction, cerebrovascular accidents, hypertension, myocardial infarction, increase in carotid intima-media thickness, generalized atherosclerosis, sudden death, and causes an overall rise in total and cardiovascular mortality.⁴⁸^,⁵⁴ Hg²⁺ exerts a toxic effect via the inactivation of the cardiovascular enzyme paraoxonase, which is employed in the oxidation of low-density lipoproteins (LDL).⁹⁴ LDL is the primary carrier of cholesterol within the cardiovascular scheme.⁶³^,¹²⁶ Slower accumulation of deoxidized LDL within the arteries characteristically favors an increase in arterial blood pressure, which consequences in hypertension and myocardial infarction or stroke.⁶³ Sherwani et al. ¹²⁷ predicted that CH₃Hg⁺ can activate phospholipase D (PLD) via oxidative stress and thiol-redox alterations, which stress the cardiovascular system. Ynalvez et al. ⁶³ reported that PLD enables the creation of COX-1-catalyzed eicosanoids and COX-2-catalyzed prostanoids, two sequences of molecules with prominent contractile impacts on cardiovascular tissue. Hong et al. ⁶⁴ studied elevated Hg contents associated with systolic and diastolic blood pressure, and abnormal lipid metabolism. A study revealed that rats chronically exposed to 200 μg/mL HgCl₂ in drinking water for 180 days exhibited an increased blood pressure.¹²⁸ Acute Hg²⁺ toxicity at concentrations of 0.5–10 μM actively induces cyclooxygenase (Cyp) and soluble epoxide hydrolase (sEH) with a consequent decrease in the cardioprotective endothelium-derived hyperpolarizing facilitator (EETs) within the cardiac muscle, leading to cardiotoxicity.⁴⁸^,¹¹⁷

Mechanism of the toxic effects of Hg²⁺ and CH₃Hg⁺ on the cardiovascular system

The mechanism by which Hg²⁺ and CH₃Hg⁺ exert profound toxic effects on the cardiovascular system is not completely clarified. All the articles mainly discussed that exposure to Hg²⁺ increases oxidative stress via the production of free radicals, and results in a reduction in the activity of antioxidant enzymes. The increase of ROS and decrease in antioxidant activity enhance the risk of progressing cardiovascular disease.⁹⁴^,¹²¹^,¹²³ CH₃Hg⁺-induced cardiotoxicity was discussed very little. Thus, further studies need to elucidate and understand this mechanism fully. Possible mechanisms for the interaction of Hg²⁺ and CH₃Hg⁺ with cardiovascular enzymes are summarized in the two pathways detailed here: production of free radicals and inactivation of antioxidant enzymes.

Mechanism 1: Production of free radicals

It was proposed that Hg²⁺ induces mitochondrial dysfunction, which arises at the ubiquinone-cytochrome B region due to the growth of free radicals, possibly because of the role of Hg²⁺ in the Fenton reaction (Fig. 4).⁴⁷^,⁹⁴^,¹²⁹ Exposure to free radicals causes the oxidation of biomolecules like proteins, lipids, nucleic acids, and LDL, which inactivate the antioxidant defense.⁴⁸ Several investigations have revealed that Hg²⁺ generates oxygen-free radicals mostly by activation of NADPH oxidase.¹³⁰^,¹³¹ The superoxide free radicals may react with NO and produce ONOO⁻ that either decrease NO production or decrease the bioavailability of NO.¹²⁴

Fig. 4 — Proposed mechanism for the toxicological effects of Hg²⁺ and CH₃Hg⁺ in endothelial cells via free radical production and inactivation of the antioxidant system.

Mechanism 2: Inactivation of antioxidant enzymes

Hg²⁺ and CH₃Hg⁺ have high affinity for –SH and/or –SeH groups, inactivating numerous sulfur and/ selenium-containing antioxidants (N-acetyl-L-cysteine, L-glutathione, alphalipoic acid), with consequent reduction of oxidant protection that increase antioxidant stress.⁹⁴ Hg²⁺ has been demonstrated to inhibit antioxidant enzymes such as Cu, manganese-superoxide dismutase (Mn-SOD), Zn-SOD, catalase, and GPx, though it is unclear exactly how Hg–SH interaction plays a part in this process. CH₃Hg-SH binding at Cys196 was demonstrated to be related with the inhibition of Mn-SOD.¹³² Furthermore, recent research shows that the inhibition of Cu, Zn-SOD, and catalase is unlikely to be caused by direct Hg-SH interaction. Hg binding to SeCys49 residue, which may cause GPx to become inactive.¹¹ Farina et al. ¹³³ demonstrated that reaction of CH₃Hg⁺ with –SH and/or –SeH groups of glutathione peroxidase (GPx) decreases Se bioavailability, which is an essential co-factor for GPx activity to break down H₂O₂ to water and other toxic peroxidation products.

Interaction of Hg²⁺/CH₃Hg⁺ with liver and kidney enzymes

Hg²⁺ in particularly damages the lining of the intestine, kidneys, and liver.⁹¹^,¹²⁹ Usually, kidneys are the principal organ that contained the highest fraction of inorganic Hg²⁺ than in any other organ of the body, resulting in nephrotoxicity.⁴⁴^,¹³⁴ Studies on kidneys from rats showed that 50% of Hg²⁺ in vivo accumulates rapidly in kidneys of rats in the interior of 3 h after contact with nontoxic 0.5 μmol/kg of HgCl₂.¹³⁵ HgCl₂ negatively affected the biosynthesis of GSH and rhodanese enzyme activity in the liver. Inactivation of GSH activity by HgCl₂ results in the generation of free radical species that prevent the role of the sulfur transferase via actions with its reactive sulfhydryl units.¹³⁶ Studies have shown that incubating 5 μmol/L HgCl₂ with 20 μmol/L homocysteine and 20 μmol/L GSH resulted in the formation of Hcy-S-Hg-S-Hcy and G-S-Hg-S-G.¹³⁷

Mechanism of Hg²⁺ induced nephrotoxicity

Within the kidneys, Hg²⁺ primarily accumulates in the proximal tubular epithelial cells of both the outer stripe and cortex of the external medulla.^138–140 It was postulated that sulfhydryl groups in renal tissue of kidney might bind this metal and might lead to an accumulation of mercuric ions. But mercury-sulfhydryl reactivity does not explain target organ selectivity since sulfhydryl groups are present in many organs.¹⁴¹ Several studies on mechanisms of proximal tubular uptake of mercury indicated that the extracellular content of GSH plays an important role in the uptake of Hg²⁺ by renal tubular epithelial cells.¹⁴¹^,¹⁴² In vivo studies on mice suggest that after renal uptake of inorganic mercury, it is supposedly transported to the lumen of proximal tubules (kidney) as GSH S-conjugates of Hg²⁺ (G-S-Hg-S-G).¹⁴³^,¹⁴⁴

Moreover, further studies were carried out in isolated brush-border membrane vesicles from the outer stripe and renal cortex of the external medulla of rats. The studies suggest that mercuric ions are removed more quickly when they bind to Cys than when they are bound to GSH or the dithiol chelator such as 2,3-dimercapto-1-propanesulfonic acid (DMPS).¹⁴⁵ Investigations using isolated diffused proximal tubules from rabbits demonstrated that luminal accumulation of Cys-S-Hg-S-Cys includes at least single Na + −dependent and single Na+-independent amino acid transporter.¹⁴⁶^,¹⁴⁷ Due to the similarity of shape and size between Cys-S-Hg-S-Cys and the amino acid cystine, it was suggested that Cys-S-Hg-S-Cys may cross the plasma membranes as a molecular mimic of cystine at the position of one or more cystine carriers sited in the luminal plasma membrane of proximal tubular epithelial cells.¹³⁷^,¹⁴⁶^,^148–150 Studies have shown evidence for the Na+-independent transfer of Cys-S-Hg-S-Cys by b0,+ system.¹⁵¹^,¹⁵² More recent studies on type II Madin–Darby canine kidney (MDCKII) cells transfected steadily with every sub-unit of b0,+ system indicated that Hcy-S-Hg-S-Hcy and Cys-S-Hg-S-Cys are movable substrates of this transporter.¹⁴⁶^,¹⁴⁸ On the other hand, it seems that a mercuric combination of GSH (G-SHg-S-G), N-acetylcysteine (NAC-S-Hg-S-NAC), and cysteinyl-glycine (CysGly; CysGly-S-Hg-SCysGly) are not carried easily by b0,+ system.¹⁴⁸ Collectively, the aforementioned data offer solid proof promoting the assumption that Cys-S-Hg-S-Cys and Hcy-S-Hg- S-Hcy rule as molecular mimics of the amino acids cystine and homocysteine respectively, at the b0,+ system.

Consequently, it is expected that one or more members of the OAT group facilitate a substantial part of the basolateral act of Hg²⁺. Diverse in vivo and in vitro analyses deliver experimental verification signifying that mercuric conjugate of Hcy, Cys, and NAC are carried out by OAT1 and/or OAT3, which have been specified in both the basolateral plasma membrane of proximal tubular epithelial cells.¹⁵³^,¹⁵⁴ OAT1 seems to be the foremost mechanism implicated in the basolateral act of Hg²⁺ into proximal tubular cells.^155–160 In fact, the latest outcomes from MDCK II cells transfected steadily with OAT1 indicated that NAC-S-Hg-S-NAC,¹⁴⁰ Cys-S-Hg-S-Cys,¹⁶¹ and Hcy-S-Hg-S-Hcy¹⁶² are transportable substrates of this carrier. Additional research using Xenopus laevis oocytes associates OAT3 with the uptake of Cys-S-Hg-S-Cys.¹⁴⁰^,¹⁶¹ Therefore, these data strongly support the assumption that OAT1 and OAT3 perform substantial functions in the basolateral uptake of chosen mercuric species.

Mechanism of CH₃Hg⁺ induced nephrotoxicity

CH₃Hg⁺ is an extremely toxic form of Hg, accumulating in the kidney and liver. Once in the systemic circulation, a strong bond is formed between CH₃Hg⁺ ion and thiol-containing molecules, for example, Cys, albumin, homocysteine (Hcy), GSH, and N-acetylcysteine (NAC).¹⁶³ Bridges and Zalups¹⁴⁹^,¹⁶⁴ postulated that thiol conjugates of methylmercury (CH₃Hg-S-Cys and CH₃Hg-S-Hcy) may mimic methionine and passage through the plasma membranes of renal proximal tubular epithelial cells by amino acid transporter, b^0,+ system. This b^{0, +} system is positioned on the luminal plasma membrane of proximal tubular epithelial cells, which was found to transport conjugates of Hg^2+.¹⁶⁴

There are also basolateral mechanisms participating the renal tubular adaptation of CH₃Hg⁺ in addition to the luminal plasma membrane mechanisms.¹⁶⁵ Findings showed that a multi-specific organic anion transporter 1 (OAT1) is confined solely in the basolateral membrane of proximal tubular epithelial cells, mediates the uptake of CH₃Hg⁺ as a conjugate of Cys-, Hcy-, NAC-, and DMPS- into proximal tubular cells.¹⁵³^,¹⁵⁴^,^166–169 Several studies excitingly demonstrated that a substantial portion of Hg in the kidneys of animals subjected to methylmercury is in Hg²⁺form^170–172 indicating that organic mercury is oxidized to inorganic mercury before or after it enters the renal tubular epithelial cells.

Interaction of Hg²⁺/CH₃Hg⁺ with Selenol-containing biomolecules

The action between Se and Hg (Hg²⁺ and CH₃Hg⁺) is one of the well-recognized cases of biological antagonism, yet the inherent mechanism rests in doubt.⁴⁰^,⁴¹^,¹⁷³ Se safeguards animals from the toxicity of both Hg²⁺ and CH₃Hg^+.³ The selenol group (-Se-H) demonstrates a pKa about three units lower than that of the -SH group (i.e. 5.2 versus 8.3) thus at physiological pH, the deprotonated, and more nucleophilic form selenolate (–Se⁻) predominates.¹⁷⁴ Hence, Hg and CH₃Hg⁺ certainly form complexes with selenol (–SeH) including biomolecules that are even more stable than their thiol analogs because of the higher nucleophilicity of –SeH.³³ Nevertheless, if this organic or inorganic Hg is bound to selenides to form HgSe(s) or highly stable –Hg–Se– protein complexes, its neuro or nephrotoxicity will be reduced. Typically, human blood consists of 0.5–2.5 μM Se that exists as selenocysteine (CysSeH). Though CysSeH is the 21st amino acid in biological schemes, free and unbound CysSeH may be existing in vivo as a degradation outcome from seleno-methionine and seleno-proteins, the bulk of CysSeH is bound in seleno-proteins as CysSeH residues.³³ Here, we provide a possible pathway that may be responsible for the Hg–Se antagonism, with an emphasis on a few key Hg–Se compounds.

A possible mechanism for Hg²⁺ and se antagonism

Since CH₃Hg⁺ complexes with thiols are kinetically very labile, biomolecules tend to produce thermodynamically more steady complexes with –SeH groups on Se-containing biomolecules.³³ The formation of an inorganic Hg–Se complex that contains approximately 100 atoms of Hg and Se may be a major mechanism of Hg detoxification.¹⁷⁵ Therefore, the presence of Se-containing biomolecules in the biological system would like to “extract” Hg²⁺ from biological thiol containing molecules to form stable selenides that are less toxic.³³

It is thus expected that Hg²⁺ may form several selenocysteine complexes e.g. Hg(SeR)₂, RS-Hg-SeR, RS-Hg-Se-SR as it has a higher affinity to selenols.³ The synthesis of Hg(SeR)₂ (R = Me, Et, or t-Bu) has been reported in the literature.¹⁷⁶ Despite the foremost attention on inorganic Hg²⁺ complexes with CysSH, no structural or thermodynamic evidence has been published for their CysSeH analogs. Thus, the characteristics of the Se–Hg compounds that are accountable for the Hg–Se antagonism remain unambiguous.³

A possible mechanism for CH₃Hg⁺ and se antagonism

Because of the abundant thiol (–SH) units in biomolecules, they have a high affinity toward CH₃Hg⁺ and easily form CH₃Hg–SR complexes.³^,³³^,¹⁷⁷ Since, CH₃Hg–SeR (–SeR = amino acids containing Se) bonding is thermodynamically stronger than that of CH₃Hg–SR¹⁷⁸^,¹⁷⁹ and the formation constants for CH₃Hg–selenol complexes are larger than their thiol analogs, ligand exchange between–SeR and–SR can take place quickly in the development of CH₃Hg–Se complexes¹⁸⁰:

Numerous CH₃Hg–Se compounds have been anticipated in the literature, comprising bis-(methyl mercuric) selenide ((CH₃Hg)₂Se) and CH₃Hg–selenocysteine. It was proven that CH₃Hg⁺ has the highest affinity for selenols (RSeH) and the trends of binding affinity of the coordination units toward methylmercury are as follows: SeH > SH > Se-Se > NH₂ > S-S, SeCH₃, SCH_3.³ NMR studies also proved that Hg–Se bonding in CH₃Hg–SeR is more stable than their sulfur counterparts because of shorter Hg–Se bond lengths.^181–184 Therefore, the formation of CH₃Hg–SeR through ligand exchange reactions in the existence of RSeH, CH₃Hg–SR complexes could reduce the toxicity of CH₃Hg⁺,¹⁸⁵ which may also reduce the bioavailability of Se in the biological system. The decrease in Se bioavailability could induce Se deficiency that is negligible in humans at the normal blood CH₃Hg⁺ level (~0.01 μM) but can be substantial in CH₃Hg⁺ exposed people. For instance, during the 1972 epidemic of CH₃Hg⁺ mass poisoning in Iraq blood CH₃Hg⁺ concentrations up to 30 μM were registered,¹⁷⁸^,¹⁸¹ which could reduce the Se bioavailability by one-third.³

Se-mediated demethylation of CH₃Hg⁺

Though toxicity of CH₃Hg⁺ to biomolecules results from its binding to -SH groups of proteins, forming CH₃HgSR complexes, CH₃Hg⁺ demethylation is also common to appear in vivo to a considerable extent in the liver with subsequent accumulation of Hg²⁺ in the kidneys in many mammals.¹⁸⁶^,¹⁸⁷ It was proposed that Hg in the blood, muscle, and brain is more commonly found as CH₃Hg⁺, whereas liver and kidneys contain high percentages of Hg^2+.¹⁸⁸ In the human brain, almost 50% of the total mercury is Hg²⁺, which noted that demethylation of CH₃Hg + is also possible in the brain,¹⁸⁹ involving those who were not revealed to high levels of Hg0.¹⁸⁷^,¹⁹⁰

A further plausible mechanism of Se-aided CH₃Hg⁺demethylation is the development of inorganic HgSe(s),¹⁹⁰^,¹⁹¹ as the existence of HgSe(s) granules has been usually narrated in the liver and kidneys of marine sea birds and mammals.¹⁹²^,¹⁹³ Recently, it has been reported that CH₃HgCys complexes are transformed into selenocysteinate [Hg(Sec)₄] complexes in multiple livers of animals (a waterbird, freshwater fish, and earthworms).¹⁹⁴ In marine mammals and seabirds, CH₃HgSR is known to be demethylated only after a threshold concentration of CH₃Hg⁺ is achieved in the system. Palmisano et al. ¹⁹⁵ proposed a two-stage mechanism for the demethylation/accumulation method of Hg in dolphin livers. They suggested that CH₃Hg⁺ was first deposited in the liver of dolphin, and demethylation took place only after a threshold level (~100 μg Hg/g) was achieved, and then released inorganic Hg²⁺ bound with Se to form HgSe(s). It should be noticed that demethylation of CH₃Hg⁺ does not essentially reduce the toxicity of Hg, since the subsequent Hg²⁺ binds to –SH containing biomolecules stronger than CH₃Hg^+,¹⁹⁶^,¹⁹⁷ and could develop toxicity unless the developed Hg²⁺ is biomineralized to HgS(s) or HgSe(s).

It was proposed that the neurotoxicity of CH₃Hg⁺ is partly due to its transportability across the BBB and for the following biotransformation to Hg²⁺ in the brain. Some studies have suggested that the neurotoxic effects of CH₃Hg⁺ may be partially mediated by the formation of inorganic Hg²⁺ in the brain through demethylation.¹⁹⁸

Gaps and perspectives

Rigorous analyses over the past few decades on the interaction of Hg with proteins have shed much light on the toxicity of Hg across a wide swath of biomolecules. However, a few significant gaps remain for the complete understanding of these interactions at the molecular level. Initially, what is the ultimate mechanism of interaction of Hg and CH₃Hg⁺ with proteins? Although both Hg²⁺ and CH₃Hg⁺ are toxic, why does Hg²⁺ have a much stronger binding affinity toward –SH sites in biological systems than CH₃Hg⁺?.³ If Hg²⁺ exists in the brain (either by CH₃Hg⁺ demethylation or by Hg0 oxidation), it would be much more neurotoxic than CH₃Hg⁺. Unfortunately, there are some gaps in the transportation of Hg²⁺ and Hg⁰ within the brain. Therefore, the production of CH₃ radicals could also be attributed to hemolysis of CH₃Hg⁺ or Se deficiency. The relative importance and validity of these diverse modes of the toxic act remain to be determined.

Dimethylmercury [(CH₃)₂Hg], is another highly toxic form of Hg, but its role of which in the biogeochemical cycle of Hg, and its bioaccumulation potential, are not well known.¹⁹⁹ Additionally, the mechanism by which Hg generates toxic effects on the cardiovascular system is not completely explained.⁹¹ Thus, much work is needed to improve the application of analytical methods for full insight into microbial uptake, export, intracellular transport and transformation, and interactions of Hg with proteins. Such molecular-level knowledge of the Hg–protein interaction is a prerequisite for the advancement of detoxification and remediation approaches intending to control Hg and protein levels in biological practices.

Conclusion

Research on the toxicity of Hg-species as well as their interaction, transportation, excretion, and the fundamental mechanism of the Hg–protein interaction is a complex and multifaceted topic as various assumptions have been anticipated. In this study, a systematic approach to the chemical nature of Hg–protein binding through the probable transportation mechanism is reviewed with a focus on Hg–protein interactions. The applications of a variety of techniques to gain insight into establishing insight into the formation of Hg–protein complexes are reviewed and potential limitations are addressed. The study showed a possible route leading to Hg–protein interactions in several organs of the body part, which could reveal the possible mechanism of Hg–protein complexes with some unsolved questions raised. Therefore, such a study is attractive for toxicological studies to develop environmental and biological research and practices.

Acknowledgment

The authors would like to acknowledge the assistance and scientific contribution from the Department of Chemistry, Comilla University, Cumilla, Bangladesh. Also, thankful to the National Plan for Science, Technology, and Innovation (MAARIFAH), King Abdulaziz City for Science and Technology, Saudi Arabia, Award Number (13NAN929-02) for supporting this work.

Contributor Information

Sharmin Akther Rupa, Department of Chemistry, Comilla University, Cumilla 3506, Bangladesh.

Md Abdul Majed Patwary, Department of Chemistry, Comilla University, Cumilla 3506, Bangladesh.

Mohammed Mahbubul Matin, Department of Chemistry, University of Chittagong, Chittagong 4331, Bangladesh.

William Emmanuel Ghann, Center for Nanotechnology, Department of Natural Sciences, Coppin State University, Baltimore, MD 21216, USA.

Jamal Uddin, Center for Nanotechnology, Department of Natural Sciences, Coppin State University, Baltimore, MD 21216, USA.

Mohsin Kazi, Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. BOX-2457, Riyadh 11451, Saudi Arabia.

Author contributions

Conceptualization, S.A.R. and M.A.M.P.; investigation, S.A.R, M.A.M.P., M.M.M. and M.K.; resources, M.K., M.A.M.P. and J.U.; data curation, S.A.R, M.A.M.P., M.M.M., and W. E. G.; writing—original draft preparation, S.A.R., M.A.M.P., and W. E. G.; writing—review and editing, all authors; visualization, M.A.M.P., and J.U.; supervision, M.A.M.P. All authors have read and agreed to the published version of the manuscript.

Conflict of interest statement: None declared.

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PERMALINK

Interaction of mercury species with proteins: towards possible mechanism of mercurial toxicology

Sharmin Akther Rupa, MS

Md Abdul Majed Patwary, PhD

Mohammed Mahbubul Matin, PhD

William Emmanuel Ghann, PhD

Jamal Uddin, PhD

Mohsin Kazi, PhD

Abstract

Graphical Abstract

Graphical Abstract.

Introduction

Fig. 1.

Toxicity owing to Hg2+/CH3Hg+

Interaction of Hg2+ and CH3Hg+ with proteins

Interaction of Hg2+ and CH3Hg+ with erythrocytes

Fig. 2.

Possible mechanism of Hg2+ poisoning in erythrocytes

Possible mechanism of CH3Hg+ poisoning in erythrocytes

Interaction of Hg2+ and CH3Hg+ with central nervous system proteins

Mechanism of Hg2+ and CH3Hg+ − induced neurotoxicity

Possible pathways of transportation of Hg2+ to CNS

Possible pathways of transportation of CH3Hg+ to the CNS

Fig. 3.

Interaction of Hg2+/CH3Hg+ with vascular and cardiovascular proteins

Mechanism of the toxic effects of Hg2+ and CH3Hg+ on the cardiovascular system

Mechanism 1: Production of free radicals

Fig. 4.

Mechanism 2: Inactivation of antioxidant enzymes

Interaction of Hg2+/CH3Hg+ with liver and kidney enzymes

Mechanism of Hg2+ induced nephrotoxicity

Mechanism of CH3Hg+ induced nephrotoxicity

Interaction of Hg2+/CH3Hg+ with Selenol-containing biomolecules

A possible mechanism for Hg2+ and se antagonism

A possible mechanism for CH3Hg+ and se antagonism

Se-mediated demethylation of CH3Hg+

Gaps and perspectives

Conclusion

Acknowledgment

Contributor Information

Author contributions

References

ACTIONS

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Toxicity owing to Hg²⁺/CH₃Hg⁺

Interaction of Hg²⁺ and CH₃Hg⁺ with proteins

Interaction of Hg²⁺ and CH₃Hg⁺ with erythrocytes

Possible mechanism of Hg²⁺ poisoning in erythrocytes

Possible mechanism of CH₃Hg⁺ poisoning in erythrocytes

Interaction of Hg²⁺ and CH₃Hg⁺ with central nervous system proteins

Mechanism of Hg²⁺ and CH₃Hg⁺ − induced neurotoxicity

Possible pathways of transportation of Hg²⁺ to CNS

Possible pathways of transportation of CH₃Hg⁺ to the CNS

Interaction of Hg²⁺/CH₃Hg⁺ with vascular and cardiovascular proteins

Mechanism of the toxic effects of Hg²⁺ and CH₃Hg⁺ on the cardiovascular system

Interaction of Hg²⁺/CH₃Hg⁺ with liver and kidney enzymes

Mechanism of Hg²⁺ induced nephrotoxicity

Mechanism of CH₃Hg⁺ induced nephrotoxicity

Interaction of Hg²⁺/CH₃Hg⁺ with Selenol-containing biomolecules

A possible mechanism for Hg²⁺ and se antagonism

A possible mechanism for CH₃Hg⁺ and se antagonism

Se-mediated demethylation of CH₃Hg⁺