Retention behavior of Hg, MeHg, thimerosal and phenylmercuric acetate on a C RP-HPLC column.

Humans are exposed to potentially toxic mercuric mercury (Hg) and methylmercury (MeHg) by the ingestion of food, to the bactericidal vaccine additive thimerosal (THI), and/or to the antifungal compound phenylmercuric acetate (PMA) which is used in some lens cleaning ophthalmic fluids. While numerous HPLC methods have been developed to separate Hg and MeHg in environmental samples (e.g.

The emerging application of LC-based metallomics techniques to unravel the bioinorganic chemistry of toxic metal(loid)s.

The on-going anthropogenic emission of toxic metal(loid) species into the environment contaminates the food supply and drinking water resources in various parts of the world. Given that inorganic pollutants cannot be degraded, their increased influx into the bloodstream of babies, children and pregnant women is inevitable. Since the ramifications of the ensuing environmental exposure on human health remain poorly defined, fundamentally new insight into their bioinorganic chemistry in organisms is urgently needed.

Interaction of carbonic anhydrase I released from red blood cells with human plasma in vitro.

Red blood cells (RBCs) constitute ∼50% of the bloodstream and represent an important target for environmental pollutants and bacterial/viral infections, which can result in their rupture. In addition, diseases such as sickle cell anaemia and paroxysmal nocturnal haemoglobinuria can also result in the rupture of RBCs, which can be potentially life-threatening. With regard to the release of cytosolic metalloproteins from RBCs into the blood-organ system, the biochemical fate of haemoglobin is rather well understood, while comparatively little is known about another highly abundant Zn-metalloprotein, carbonic anhydrase (CA I).

Toward a Mechanism-Driven Integrated Framework to Link Human Exposure to Multiple Toxic Metal(loid) Species with Environmental Diseases.

The ongoing anthropogenic pollution of the biosphere with As, Cd, Hg and Pb will inevitably result in an increased influx of their corresponding toxic metal(loid) species into the bloodstream of human populations, including children and pregnant women. To delineate whether the measurable concentrations of these inorganic pollutants in the bloodstream are tolerable or implicated in the onset of environmental diseases urgently requires new insight into their dynamic bioinorganic chemistry in the bloodstream-organ system. Owing to the human exposure to multiple toxic metal(loid) species, the mechanism of chronic toxicity of each of these needs to be integrated into a framework to better define the underlying exposure-disease relationship.

Mercury binding to proteins disclosed by ESI MS experiments: The case of three organomercurials.

Solution interactions of three organomercury compounds, i.e., methylmercury chloride, thimerosal and phenylmercury acetate, with a group of biochemically relevant proteins, namely cytochrome c (Cyt c), ribonuclease A (RNase A), carbonic anhydrase I (hCA I), superoxide dismutase (SOD), and serum albumin (HSA), were investigated using an established ESI MS approach.

N-Acetylcysteine Displaces Glutathionyl-Moieties from Hg and MeHg to Form More Hydrophobic Complexes at Near-Physiological Conditions.

The anthropogenic release of Hg is associated with an increased human exposure risk. Since Hg and MeHg have a high affinity for thiols, their interaction with L-glutathione (GSH) within mammalian cells is fundamentally involved in their toxicological chemistry and excretion. To gain insight into the interaction of these mercurials with multiple small molecular weight thiols, we have investigated their competitive interactions with GSH and N-acetylcysteine (NAC) at near-physiological conditions, using a liquid chromatographic approach.

Translational toxicology of metal(loid) species: linking their bioinorganic chemistry in the bloodstream to organ damage onset.

The quantification of arsenic, mercury, cadmium and lead in the human bloodstream is routinely used today to assess exposure to these toxic metal(loid)s, but the interpretation of the obtained data in terms of their cumulative health relevance remains problematic. Seemingly unrelated to this, epidemiological studies strongly suggest that the simultaneous chronic exposure to these environmental pollutants is associated with the etiology of autism, type 2 diabetes, irritable bowel disease and other diseases. This from a public health point of view undesirable situation urgently requires research initiatives to establish functional connections between human exposure to multiple toxic metal(loid) species and adverse health effects.

More Effective Mobilization of Hg from Human Serum Albumin Compared to Cd by L-Cysteine at Near-Physiological Conditions.

Although chronic low-level exposure to Hg and Cd causes human nephrotoxicity, the bioinorganic processes that deliver them to their target organs are poorly understood. Since the plasma protein human serum albumin (HSA) has distinct binding sites for these metal ions, we wanted to gain insight into these translocation processes and have employed size-exclusion chromatography coupled on-line to an inductively coupled plasma atomic emission spectrometer using phosphate-buffered saline mobile phases. When HSA 'labeled' with Hg and Cd (1:0.

Physiologically relevant hCys concentrations mobilize MeHg from rabbit serum albumin to form MeHg-hCys complexes.

Methylmercury (MeHg) is one of the most potent neurotoxins to which humans are exposed via the consumption of fish, from which it is effectively absorbed via the gastrointestinal tract into the bloodstream. Its interactions with plasma proteins, small-molecular-weight (SMW) molecules, and red blood cells, however, are incompletely understood, but critical as they determine whether and how much MeHg reaches target organs. To better define the role that SMW thiols play in the delivery of MeHg to known transporters located at the placental and blood-brain barrier, we have employed size exclusion chromatography-inductively coupled plasma-atomic emission spectroscopy to analyze MeHg-spiked rabbit plasma in the absence and presence of SMW thiols dissolved in the phosphate-buffered saline buffer mobile phase.

Quantification of human plasma metalloproteins in multiple sclerosis, ischemic stroke and healthy controls reveals an association of haptoglobin-hemoglobin complexes with age.

Advanced analytical methods play an important role in quantifying serum disease biomarkers. The problem of separating thousands of proteins can be reduced by analyzing for a 'sub-proteome', such as the 'metalloproteome', defined as all proteins that contain bound metals. We employed size exclusion chromatography (SEC) coupled to an inductively coupled plasma atomic emission spectrometer (ICP-AES) to analyze plasma from multiple sclerosis (MS) participants (n = 21), acute ischemic stroke (AIS) participants (n = 17) and healthy controls (n = 21) for Fe, Cu and Zn-metalloproteins.

Toxic Metal Species and 'Endogenous' Metalloproteins at the Blood-Organ Interface: Analytical and Bioinorganic Aspects.

Globally, human exposure to environmental pollutants causes an estimated 9 million deaths per year and it could also be implicated in the etiology of diseases that do not appear to have a genetic origin. Accordingly, there is a need to gain information about the biomolecular mechanisms that causally link exposure to inorganic environmental pollutants with distinct adverse health effects. Although the analysis of blood plasma and red blood cell (RBC) cytosol can provide important biochemical information about these mechanisms, the inherent complexity of these biological matrices can make this a difficult task.

South Australian Medicines Evaluation Panel in review: providing evidence-based guidance on the use of high-cost medicines in the South Australian public health system.

Objective The South Australian Medicines Evaluation Panel (SAMEP) was established in 2011 to make evidence-based recommendations on the funding of high-cost medicines in South Australian public hospitals via a high-cost medicines formulary. SAMEP represents one component of South Australia's process for state-based health technology assessment (HTA). The aim of this study was to describe the experience of SAMEP in the context of Australia's complex governance model for hospital-based care.

Linking molecular targets of Cd in the bloodstream to organ-based adverse health effects.

The chronic exposure of human populations to toxic metals remains a global public health concern. Although chronic Cd exposure is linked to kidney damage, osteoporosis and cancer, the underlying biomolecular mechanisms remain incompletely understood. Since other diseases could also be causally linked to chronic Cd exposure, a systems toxicology-based approach is needed to gain new insight into the underlying exposure-disease relationship.

Application of a Novel Metallomics Tool to Probe the Fate of Metal-Based Anticancer Drugs in Blood Plasma: Potential, Challenges and Prospects.

Although metallodrugs are used to treat a variety of human disorders and exhibit a remarkable diversity of therapeutic properties, they constitute only a tiny minority of all medicinal drugs that are currently on the market. This undesirable situation must be partially attributed to our general lack of understanding the fate of metallodrugs in the extremely ligand-rich environment of the bloodstream. The challenge of gaining insight into these bioinorganic processes can be overcome by the application of 'metallomics tools', which involve the analysis of biological fluids (e.

Sample preparation of blood plasma enables baseline separation of iron metalloproteins by SEC-GFAAS.

The analysis of human plasma for biomarkers holds promise to revolutionize disease diagnosis, but is hampered by the inherent complexity of the plasma proteome. One way to overcome this problem is to analyze plasma for a sub-proteome, such as the metalloproteome. Previous studies employing size-exclusion chromatography (SEC) coupled on-line to an inductively coupled plasma-atomic emission spectrometer (ICP-AES) have revealed that plasma contains ~12 copper, iron and zinc metalloproteins.

SEC hyphenated to a multielement-specific detector unravels the degradation pathway of a bimetallic anticancer complex in human plasma.

The bimetallic metal complex Titanocref exhibits relevant anticancer activity, but it is unknown if it is stable to reach target tissues intact. To gain insight, a pharmacologically relevant dose was added to human blood plasma and the mixture was incubated at 37 °C. The obtained mixture was analyzed 5 and 60 min later by size-exclusion chromatography hyphenated to an inductively coupled plasma atomic emission spectrometer (SEC-ICP-AES).

Identification of a haptoglobin-hemoglobin complex in human blood plasma.

Blood plasma metalloproteins that contain copper (Cu), iron (Fe), zinc (Zn) and/or other metals/metalloids are potential disease biomarkers because the bloodstream is in permanent contact with organs. Their quantification and/or the presence of additional metal-entities or the absence of certain metalloproteins in blood plasma (e.g.

Development and validation of the Medication Regimen Simplification Guide for Residential Aged CarE (MRS GRACE).

Background: Residents of aged care facilities use increasingly complex medication regimens. Reducing unnecessary medication regimen complexity (eg, by consolidating the number of administration times or using alternative formulations) may benefit residents and staff.

Objective: To develop and validate an implicit tool to facilitate medication regimen simplification in aged care facilities.

Improving the safety of metal-based drugs by tuning their metabolism with chemoprotective agents.

Metal-based drugs remain a tiny minority of all drugs that are on the market. The success story of the quintessential metal-based drug cisplatin (CP), which is intravenously administered to 70% of all cancer patients, however, demonstrates the inherent potential of metal-based drugs. A distinct disadvantage of CP is the dose-limiting severe toxic-side effects that it exerts in patients.

Selenium-mediated arsenic excretion in mammals: a synchrotron-based study of whole-body distribution and tissue-specific chemistry.

Arsenicosis, a syndrome caused by ingestion of arsenic contaminated drinking water, currently affects millions of people in South-East Asia and elsewhere. Previous animal studies revealed that the toxicity of arsenite essentially can be abolished if selenium is co-administered as selenite. Although subsequent studies have provided some insight into the biomolecular basis of this striking antagonism, many details of the biochemical pathways that ultimately result in the detoxification and excretion of arsenic using selenium supplements have yet to be thoroughly studied.

Remarkable differences in the biochemical fate of Cd, Hg, CHHg and thimerosal in red blood cell lysate.

Humans are environmentally exposed to potentially toxic Cd and Hg species and to the Hg compound thimerosal (THI), an antibactericidal vaccine additive. Previous studies have revealed that Cd, Hg and CHHg are taken up by red blood cells (RBCs) and bind to cytosolic glutathione (GSH) and/or hemoglobin (Hb). Since interactions in the cytosol of RBCs may be linked to their hemolysis, a more comprehensive characterization of these interactions was sought.

Environmentally relevant concentrations of aminopolycarboxylate chelating agents mobilize Cd from humic acid.

Although Cd is a pollutant of public health relevance, many dietary sources from which it can be absorbed into human tissues remain unknown. While it is well established that the biogeochemical cycle of Cd involves its complexation with environment-derived ligands (e.g.

Probing the interaction of bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes with glutathione and rabbit plasma.

Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes, [{Pt(terpy)}μ-(X)] (where X is a linker) with glutathione (GSH) by means of H and Pt NMR spectroscopy were investigated.