Chemical foundation of the attenuation of methylmercury(II) cytotoxicity by metallothioneins

Abstract

To elucidate the chemical interactions underlying the role of metallothioneins (MTs) in reducing the cytotoxicity caused by MeHg(II), we monitored in parallel by electronic absorption and CD spectroscopies the stepwise addition of MeHgCl stock solution to mammalian Zn 7 -MT1 and the isolated Zn 4 -aMT1 and Zn 3 -bMT1 fragments. The incorporation of MeHg + into Zn 7 -MT and Zn 3 -bMT entails total displacement of Zn (II) Mercury is a widespread contaminant that enters the environment from a variety of sources including industrial processes and hazardous waste sites. The ability of aquatic micro-organisms to convert metallic mercury into the methylmercury(II) cation (MeHg + ) is the key to its accumulation in fish, which then become a common source of exposure of humans to MeHg + [1,2]. Whereas the damaging pathological and biochemical consequences of MeHg + in humans have long been known, current studies are focusing on the effects of MeHg + on the central nervous system [3] and male fertility [4]. In both cases, a role for metallothioneins (MTs) in attenuating the cytotoxicity caused by MeHg + has been proposed [5][6][7]. A main feature of MTs, a family of ubiquitous low molecular mass proteins, is their extremely high content of cysteine residues. These bind to metal centers enabling them to serve as a heavymetal-detoxification system [8]. Considering the abundance of MTs in the central nervous system and the preference of Hg(II) ions for soft sulfur ligands, the study of MeHg-MT species from a chemical perspective is warranted.Although the interaction of MTs with Hg(II) ions has long been established [9], elucidation of the binding features of Hg-MT species has been hampered by the inherent difficulties of Hg(II) thiolate chemistry, which mainly arise from the diverse coordination preferences of Hg(II) and the various ligation modes of the thiolate ligands [10,11]. Nevertheless, the analysis of Hg(II) binding to MTs has been intensively studied [9]. In contrast, the chemistry of MeHg(II)-MT complexes has attracted much less attention. Earlier studies found MT to have no significant role in the detoxification of MeHg + [12] and to be unable to bind to MeHg + either in vivo or in vitro [13]. Subsequent attempts to induce brain MT by exposure to MeHg + gave inconsistent results: MT concentrations remained unchanged in rats [14,15], whereas MT and mRNA concentrations increased in MeHg + -treated rat neonatal astrocyte cultures [16]. However, there is mounting evidence that induction of MTs in astrocytes attenuates and even reverses the cytotoxicity caused by MeHg + [5,6], indicating binding of MeHg + by an astrocyte-specific MT isoform, MT1 [17].Existing data on Hg(II)-MT species cannot be extended to MeHg-MT complexes mainly because of the different coordination chemistry of Hg(II) and MeHg + towards thiolate ligands and thus towards the cysteine residues responsible for metal coordination in MTs. The coexistence of digonal, trigonal-planar and tetrahedral coordination geometries together with the presence of se...

Comparative toxicogenomic responses of mercuric and methyl-mercury

“…The present study is the first to report a down-regulation of metallothionein gene expression in response to MeHgCl exposure. Although earlier studies showed that metallothioneins were incapable of binding methylmercury [45], more recent work indicated that metallothioneins could bind methylmercury [46]. In addition to binding metals, metallothioneins are also important in regulating the redox status of cells and preventing intracellular oxidative damage.…”

Rhenium and technetium tricarbonyl, {M(CO)3}+ (M = Tc, Re), binding to mammalian metallothioneins: new insights into chemical and radiopharmaceutical implications

“…Finally, this work extends the available information on the reactivity of MTs towards organometallic compounds, since, up to the present, the reported studies on the binding capabilities of MTs have been limited to several inorganic metal cations and, as far as we know, only one work with methyl mercury has been published [29]. Furthermore, considering that the coordination about the metal in the {fac-M(CO) 3 } + fragments should be octahedral-d 6 configuration for Tc(I), Re(I), the geometry of the three vacant coordination sites about M is going to be different to all the other metal-coordinating geometries previously studied with MTs.…”

Metallomics of Mercury: Role of Thiol‐ and Selenol‐Containing Biomolecules

“…The complex was later identified to be CH 3 HgSCys by the aforementioned HPLC-ICP/ESI-MS technique (Lemes and Wang, 2009). XAS has also been successfully used in identifying the bonding environment of Hg 2+ and CH 3 Hg + with sulfur-containing proteins such as MTs (Stillman, 1995;Leiva-Presa et al, 2004). Most recently, XAS analysis of human brain samples following MeHg poisoning or environmental exposure has confirmed the presence of inorganic and methyl Hg complexes with thiols and selenols, as well as HgSe nanoparticles (Korbas et al, 2010).…”

“…The formation of Hg m -MT with m up to 18 has been reported, where Hg 2+ binding can be via various Hg(SCys) n (n = 2-4) environments (Stillman, 1995). CH 3 Hg + binding with MTs is, however, less well known, but the affinity of MTs for CH 3 Hg + seems to be much weaker than for Hg 2+ , and the binding is most probably via a diagonal CH 3 HgSCys environment (Leiva-Presa et al, 2004).…”