Organic Derivatives of Mercury and Tin as Promoters of Membrane Lipid Peroxidation

The toxicity mechanisms of mercury and tin organic derivatives are still under debate. Generally the presence of organic moieties in their molecules makes these compounds lipophilic and membrane active species. The recent results suggest that Hg and Sn compounds deplete HS-groups in proteins, glutathione and glutathione-dependent enzymatic systems; this process also results in the production of reactive oxygen species (ROS), the enhancement of membrane lipids peroxidation and damage of the antioxidative defence system. The goal of this review is to present recent results in the studies oriented towards the role of organomercury and organotin compounds in the xenobiotic-mediated enhancement of radical production and hence in the promotion of cell damage as a result of enhanced lipids peroxidation. Moreover the conception of the carbon to metal bond cleavage that leads to the generation of reactive organic radicals is discussed as one of the mechanisms of mercury and tin organic derivatives toxicity. The possible use of natural and synthetic antioxidants as detoxification agents is described. The data collected recently and presented here are fundamentally important to recognizing the difference between the role of metal center and of organic fragments in the biochemical behavior of organomercury and organotin compounds in their interaction with primary biological targets when entering a living organism.


INTRODUCTION
Due to the widespread use of the organometallic compounds RnMXm, in particular organomercuriais RHgX,. R2Hg and organotins RnSnX4., (n 0 4), a considerable amount of these highly toxic xenobiotics enters various ecosystems /1/. The accumulation of RnMXm in biota leads to a phenomenon relevant to toxicants transfer to higher organisms and therefore their extremely hazardous impact on human health and on the environment is a matter of great concern/2,3/.
Within the class of organometallic ecotoxicants, RnMXm, there are considerable variations in toxicity depending both on the nature of metal atom M, number and nature of the organic groups R and the nature of species formed in various media. Generally the presence of organic moieties in their molecules makes these compounds lipophilic and membrane active species/4,5/. Organic derivatives of Hg and Sn are supposed to induce membrane associated oxidative stress in living organism through different mechanisms including the possibility to enhance the intracellular generation of reactive oxygen species, H202, 02 , HO (ROS)/6-8/.
It is well known that Hg and Sn compounds deplete HS-groups in proteins and glutathione; this process also results in the production of ROS/7,9/. Enhanced lipid peroxidation, DNA and sulfhydryi homeostasis damage, the decrease of total glutathione level, the inhibition of superoxide dismutase, catalase, glutathione reductase, Se-dependent and Se-independent glutathione peroxidases, glutathione S-transferases and perturbation of antioxidant defense system are the consequences of this impact/10,11/. However, little is known about the molecular mechanisms of organometallics action as exogeneous prooxidant stressors. To understand the biomolecular mode of organomercury and organtin compounds action as promoters of cellular oxidative stress, the participation of various R, MXm in key biochemical processes responsible for the extensive lipids peroxidation and damage of the antioxidative defence system should be studied.
The interaction of organic derivatives of heavy metals with free sulfhydryl groups in proteins that leads to the metal-induced cell death is,well known/12/. The involvement of R,MX,, (with general formula R,M) in oxidative/free radical reactions, namely in radical chain oxidation of the biological substrate R'H, is purely investigated (Fig. I). The interaction of R,,M may include the reactions either with peroxyl radicals R'OO or with hydroperoxides R'OOH that are main intermediates of R'H oxidation and lead to the homolytic cleavage of C-M bonds and result in the formation of reactive organic radicals R" responsible for the enhanced lipid peroxidation and cell death. The goal of this review is to present recent results in the studies oriented towards the role of organomercury and organotin compounds in the xenobiotic-mediated enhancement of radical production and hence in the promotion of cell damage as a result of enhanced lipids peroxidation. Moreover the conception of the carbon to metal bond cleavage will be discussed as one of the mechanisms of mercury and tin organic derivatives cytotoxcity and the possible use of natural and synthetic antioxidants as detoxification agents will be described. VoL Z Nos. [1][2]2004 Organic .Derivatives ofMercwT and Tin as Promoters of Membrane Lipid Peroxidation

TOTAL LIPIDS CONTENT AS A BIOMARKER OF ORGANOMETALLICS INDUCED OXIDATIVE MEMBRANE DAMAGE
Xenobiotic-induced lipids peroxidation, as a critical stage in toxicological processes, describes the nonenzymatic oxidative destruction of fats /11/. The peroxidation of unsaturated fatty acids (oleic, linoleic, linolenic, arachidonic acids) in membrane lipid bilayer leads to the membrane cells damage/9/. The decrease of the membrane fluidity and potential, permeability to H and Ca 2+ ions is observed as a result of lipids peroxidation.
It has been observed that the presence of 0.15 ppb [(n-C4H9)3Sn]20 caused a highly significant decrease in the total lipids content in body tissues (digestive gland, gills and foot) of the estuarine edible clam, Anadara rhombea /13/. Acute (0.05 ppb) and chronic (0.02 ppb) exposures to [(n-C4Hg)3Sn]20 induced various changes in vital biochemical systems in A. rhombea. The change of the lipids content might be explained as a consequence of the degradation of the unsaturated fatty acids mediated by organotins. The influence of (C6Hs)3SnCI and (C6Hs)zSnCI2 on the fatty acids composition in a marine chlorophyte, Dunaliella tertiolecta Butcher and a marine diatom, Skeletonema costatum (Greville) Cleve, which exhibit different resistances to phenyltins, were studied in the period of 72 h/14/. The proposition that sensitivity to phenyltin compounds is related to their fatty acid composition has been confirmed when attempts were made to grow D. tertiolecta in the presence of (C6Hs)3SnCI ranging in concentration from 2.1.10 ' to 2.1.10 gM, and S. costatum in the presence of (C6Hs)3SnCI and (C6Hs)2SnCI2 in concentrations ranging from 8.4.10 .5 to 8.4.10 .3 IuM and 8.4.10 -3 to 8.4.10 1 IaM respectively. The results show a 45% increase in monounsaturated fatty acids with a decrease in total polyunsaturated fatty acids that are more easily oxidized substrates.
Enhanced lipid peroxidation in liver, kidney and brain of mice has been observed after exposure to CH3HgCI (10-40 mg/l in drinking water) for 2 weeks /15/. An increase in catalase and glutathione Stransferase (GST) activities was observed in the sheaths of the marine phanerogam Posidonia oceanica (L.) Delile experimentally exposed to inorganic mercury/16/indicating that the antioxidant mechanisms were overtaxed and could not prevent membrane lipid peroxidation. The effect of HgCI2 on lipid profiles in organs of freshwater cat-fish (Heteropneustes fossilis) was studied/17/. The daily exposure of HgCI2 0.2 mg/L for 10, 20 and 30 days depleted the total lipids in brain. The content of phospholipids enhanced significantly in 30 days. Liver exhibited elevated levels of total lipids. Kidney showed a marked decrease in the content of total lipids at higher exposure to HgCI2. The content of total lipids and phospholipids was high in muscle. The membrane lipids composition markedly influences membrane permeabilisation/18/. The direct toxic effect of (n-C4H9)3SnC1 on growth of Saccharomyces cerevisiae was inhibited by the enrichment of cells with linoleic acid. Since the cellular response to organometallic compounds exposure might be influenced by the supplementation with fatty acids the stability of organs and tissues is expected to depend on their total content in lipids/19/.
The effect of (n-C4H9)3SnCI observed in the study of two species of amphipods, Rhepoxynius abronius Barnard (Phoxacephalidae) and Eohaustorius estuarius Bosworth (Haustoriidae), commonly used in sediment bioassays, showed that the decrease in whole-body lipid content may be an indicator of declining animal health (and increased sensitivity to toxicants)/20/.

Bioinorganic Chem&try and Applications
A comparative study on the interactions between R2SnCI2, R3SnCI (R alkyl or phenyl groups) and model bilayer lipid membranes has been performed using the relative degree of depolarization of the lipid membrane potential as a parameter of the toxicity/21/. The high lipophilic R3SnCI were the most active species. It was shown that a correlation exists between depolarization activity and the lipophilicity of R3SnC1 hydrolysis products. The surface charge of modified membranes had a secondary influence on depolarization efficiency of organotin compounds /22/. The interaction of (n-CaH9)3SnCI and (C6Hs)3SnCI with model membranes composed of different phosphatidylethanolamines has been studied by means of differential scanning calorimetry, X-ray diffraction, NMR 31p and IR spectroscopy /23/. It has been shown that (n-C4Hg)3SnCI and (C6Hs)3SnC! segregate.in phosphatidylethanolamine membranes and disrupt the pattern of H-bonding in the interfacial region of dielaidoyiphosphatidylethanolamine membranes. The authors proposed that the specific toxic effects of organotins might be exerted through the alteration of membrane function produced by interaction of (n-CaH9)3SnCI and (C6Hs)3SnCI with the lipids component of the membrane.
The results of various experimental studies show that the degradation of lipids is one of the possible mechanisms involved in organometallics toxicity.

PEROXIDATION OF UNSATURATED FATTY ACIDS IN THE PRESENCE OF ORGANOMETALLICS
The influence of organometallic compounds RHgX, R2Hg, R,SnX4., bearing various organic groups R upon the lipid peroxidation level was studied using unsaturated fatty acids model compoundsoleic acid and methyl oleate as substrates R'H/24-27/.
The monitoring was performed at various temperatures by measuring the total concentration of isomeric hydroperoxides R'OOH and the concentration of thiobarbituric acid reactive substances (TBARS), namely malonic dialdehyde (MDA), as a marker of the carbonyi compounds formation following the hydroperoxides decomposition/28/. The difference in substrate modification (oleic acid or its methyl ester) does not affect the kinetic data of R'OOH formation/24/; therefore the interaction of organometallic compounds with the carboxylic group in oleic acid might be omitted.
The kinetic data for the oleic acid oxidation (rate constants of R'OOH accumulation k and relative change in R'OOH concentrations A) in the presence of organomercury and organotin compounds presented in Table  show  between the interaction of RnMXm with either peroxyl radicals or hydroperoxides is expected to be a cause of their different action. Indeed at 37C the accumulation of R'OOH is a slow process (rate constant-Vol. 2, Nos. . [1][2]2004 Organic The relative change in R'OOH concentrations (Ai) in the presence of organomercurials at temperature 37C is 50% of the corresponding values for substrate's autooxidation. On the other hand the value of Ai for carbonyl compounds accumulation in the presence of organomercurials shows a 3-4 time increase when compared with the corresponding values of substrate autooxidation. Therefore at 37C RHgX, R2Hg have a prooxidative activity. At temperature > 50C the rate constants for R'OOH formation are higher than the corresponding parameters for R'OOH decomposition. In this region RHgX, R2Hg interact with the excess of active oxygen-centered peroxyl radicals R'OO in S.2 reaction/30/(Eq. 3,4).
The SH2 process might be synchronic or might include the formation of the metal-centered radical The loss of R group during the oxidative destruction of (C6Hs)2Hg in oleic acid has been confirmed by using IR spectroscopy/25/. Fig. 2 represents a change of the absorption bands corresponding to the Hg-C bond frequencies at 400-500 cm1. The initial spectrum shows the absorption band at 462 cm ( Fig. 2, a) which correspond to C-Hg bond in disubstituted organomercury compound R2Hg. The loss of the intensity of this band and appearance of a new band at 453 cm (Fig. 2 The R'OOH formation rate constants k and the values of R'OOH concentrations relative changes A increase with the number of R groups in R,SnX4_, at 37C, as can be clearly seen in Table I. However at 60C the rates of hydroperoxides formation and the rate of their decomposition become close; kinetic curves form typical for radical chain processes, and the participation of RnSnX4., in the interaction with R'OOH seems to play an important role (Eq. 9).
R'OOH + RnSnX4_, RnSnX3.,(OOR')+ HX At 90C protolytic decomposition of RnSnX4.n is a major process and the dependence of R'OOH accumulation on the number of R groups in R,SnX4., takes the opposite character. Fig. 3 presents the kinetic curves of R'OOH accumulation in the presence of ethyl derivatives of tin.
The reactions (1-9) involve the formation of organometallic peroxides which are unstable and may give various radical intermediates/31/promoters of further radical chain processes. Moreover the generation of metal-centered radicals that interact easily with dioxygen to produce oxygen-centered radicals is also expected. The reactions of the membrane-active (n-CaH9)3SnX (X OCH3, CI, Br, I) with O.'have been investigated in the aprotic solvent system [cis-dicyclohexano-18-crown-6 ether DMSO] using ESR /32/. Conductivity measurements of (n-CaHg)3SnX solutions demonstrate that these compounds dissociate to produce (n-CaH9)3Sn cations which interact with O,' to give (la-superoxo)bis(tributylstannyl) radicals. The authors /32/ proposed that la-superoxo radical complexes play the key role in the initiation of lipid peroxidation processes in vivo.

THE IMPACT OF ORGANOMETALLICS ON PHOSPHOLIPIDS
The explanation of the biochemical mode of organometallic compounds action (including organic derivatives of Hg and Sn) follows the concept of the interaction of metal center with electron-donor heteroatoms in biologically important substrates /1,5,33/. From this point of view, phosphoryl-containing fragments, e.g. anionic phosphodiester groups (OPO), are important moieties in phosphor-and phosphonolipids/34/. From the study of the dimer of bis[(di-n-butyi-3,6-dioxaheptanoato)tin] and tri-n-butyltin-3,6,9trioxodecanoate with calf thymus DNA samples it was proposed that both organotin compounds do interact with DNA, probably at the level of the phosphate groups/35/. The ability of phenyltin compounds to induce structural changes in the phosphatidylcholine bilayers has been studied by NMR Hand P spectroscopy in the presence of dodecyltrimethylammonium chloride, bromide and iodide. The presence of the surfactant influences the interaction of phenyltins with model membranes and the changes are dependent on the kind of the counter-ion/36/. The alteration in lipid profiles induced by mercury has been shown to be time-dependent /17/. The content of phospholipids in brain of catfish enhanced significantly at 30 days. Liver exhibited elevated levels of total lipids, phospholipids and cholesterol. By using human HL-60 leukemia cells, it was shown that (n-C4Hg)2SnCI2 and (CH.)3SnCI induce arachidonic acid liberation or its rearrangement within the phospholipids before a loss in viability can be detected and an increase of free fatty acid and eicosanoids before cell death could be detected /37/. Primarily affected is phosphatidylethanolamine which loses arachidonic acid and, to a minor extent, phosphatidylcholine. The study oriented towards the definition of the E. Milaeva et al.
Bioinorganic Chemistry andApplications mechanism by which CH3HgC! induces human T-cell apoptosis shows that cardiolipin, a mitochondrial phospholipid, was oxidized/38/. The complexation of RnSnX4_, (n 1-3) with phosphodiester fragments of the lipid bilayer might be the key step in the interaction of organotins with cell membranes. In that case phospholipids are supposed to play a protective role, preventing toxic organotin compounds from penetrating the cells and intracellular components. However, this mechanism does not include the possible carbon to metal bond cleavage.
In order to prove the assumption that the formation of reactive radical species following the homolytic cleavage of C-Sn bond might be the cause of a toxic action of R, SnXm the synthesis of organotin complexes with phosphocholine (PC) and dimyristoyl-L-ot-phosphatidylcholine DMPC) as model structural components of lipids has been achieved and their influence on the oleic acid peroxidation has been studied/27,39/.
Figs. 4a, 4b show the kinetic curves of the R'OOH accumulation in the presence of methyl derivatives of tin (CH3)nSnCI4_n and their complexes with phosphocholine [(CH3).SnCI4.. ]kePC at 37C. The coordination of organotin molecules to the phosphocholine moieties does not influence significantly the accumulation of oleic acid hydroperoxides. This experimental fact allows suggesting that the first step of organotins interaction with lipids fragment does not prevent the activity of these compounds in radical processes of lipids peroxidation. Therefore the effect of organotin compounds on cellular membranes may be dependent upon both the complexation with membrane fragments and the participation in radical/oxidative processes that leads to the disturbance of lipids bilayer and membrane damage. Organic Derivatives of Mercury and 17n as Promoters of Membrane Lipid Peroxidation

LIPID PEROXIDATION IN THE PRESENCE OF ORGANOMETALLICS IN VITRO AND IN VIVO
The data illustrated with the examples of organomercury-and organotin-mediated oxidative damage to the principal components of the membrane bilayers, confirm the mechanistic concepts on the capacity of RHgX, R2Hg, RnSnX4_, to generate reactive oxygen species and other active organic intermediates under physiological conditions/40/. Their redox and radical reactivity may underlay the mechanism of mediation of oxidative damage to cell constituents. Treatment of the hypothalamic neural cells with methylmercury salt (10 IaM for 3 h and 5 tM for 24 h) results in increased formation of ROS, and 20% and 56% cell death respectively/41/. These data suggest that methylmercury-mediated cell killing correlates closely with ROS generation. A significant increase in the ROS formation rate in rat brain was detected 7 days after the injection of CH3HgX (5 mg/kg) /42/. The formation of oxygen-centered radical species has several biochemical consequences; some of them include the interaction of ROS with carbonor metal-centered radicals formed in biodegradation of RnMXm.
An in vivo and in vitro comparative analysis of the influence of methyl mercury salts on the lipid peroxidation as a biomarker of the oxidative stress of the organism has been performed. The in vivo experiments with rats as testing organisms show the promotion of lipids peroxidation monitored by TBARS (MDA) concentration's increase when rats were pretreated by intraperetonial injection with CH3HgNO3 (5 mg/kg weight)/43/ (Table 2). in the presence of methylmercury nitrate correspondingly; 4 animals were investigated in each group of experiments; enzymatic peroxidation level was measured as spontaneous process, non-enzymatic peroxidation level was measured by addition of ascorbic acid and More salt; haemolysis of erythrocytes was monitored by addition of H2Oz. ** Non-enzymatic peroxidation level was measured after addition of CCI3COOH.
The in vitro experiments with rat liver homogenates show that CH3HgI stimulates lipids peroxidation monitored by increase in MDA (Table 3). 8O E. Milaeva et al. The lipid peroxidation level in liver of fish samples of Russian sturgeon (Acipenser guendelstaedti B.) was studied in the presence of (CH3)3SnCI (Table 4) and at various concentrations of CH3Hgl (Fig. 5)/44/as a biomarker of adaptation potential of the organism/45/.

Bioinorganic Chemistry and Applications
Vol. 2, Nos. [1][2]2004 Organic Derivatives of Mercury and Tin as Promoters of Membrane Lipid Peroxidation Table 4 The peroxidation level in fish liver homogenates ofAcipenser guendelstaedti B. Dependence of lipids peroxidation level in vivo in liver homogenates of Russian sturgeon (Acipenser guendelstaedti B.) on the content of CH3HgI: (1) non-enzymatic peroxidation level was measured by addition of ascorbic acid and More salt; (2) enzymatic peroxidation level was measured as spontaneous process, (3) non-enzymatic peroxidation level was measured after addition of CCI3COOH.

NATURAL AND SYNTHETIC ANTIOXIDANTS AS ANTIDOTES AGAINST ORGANOMETALLICS TOXIC EFFECTS
The involvement of lipophylic organometallic compounds in cellular radical and redox processes means the promotion of membrane bilayer oxidative destruction due to the generation of ROS and other active radical species. These events might be prevented or inhibited by the antioxidants present in living organisms. Cellular self-defense response is manifested by increase of the antioxidant enzyme activities (glutathione peroxidase, glutathione reductase, glutathione transferase, superoxide dismutase, catalase, etc.). However there is strong evidence that intoxication with organic derivatives of Hg and Sn causes a disturbance in the antioxidative defense system as well/6,11/.
It is a well-known fact that methylmercury cation CH3Hg + interacts with glutathione in human blood, leading to glutathione level depletion and enhancement of oxidative stress/46/. Moreover, the decrease of vitamins E and C contents was observed, for instance, in rat kidney after 12 h administration of mercury compounds /47/. The changes in glutathione-dependent enzyme activities were studied as effects of oral exposure to (C6Hs)3SnOCOCH3 for 70 days on hepatic and renal enzymes involved in glutathione metabolism in rabbits and lambs /48/. The inhibition of glutathione S-transferases isolated from larval midguts, Spodoptera frugiperda, by (C6Hs)3SnCI has been detected /49/. The authors suggest that the depression of glutathione S-transIrase and glutathione peroxidase is one part of the complex mechanism of organotins cytotoxicity. By using a flow cytometry study it was shown that n-C4H9)3SnC! induces a change in cellular level of glutathione in rat thymocytes/50/. Since the mechanism of glutathione level decrease by RnMXm is supposed to include the interaction of metal with S atoms, the sulfur-containing agents can be used as antidotes. Among them dimercaptocompounds (2,3-dimercaptopropane-l-sulfonic acid, meso-2,3-dimercaptosuccinic acid, diethyldithiocarbamate, monoisoamyl meso-2,3-dimercaptosuccinate) show a significant protective effect on the toxicity of organotins and organomercurials/51-53/.
On the other hand the cascade of radical reactions following the accumulation of active species formed due or from the organometallics biodegradation activates chain radical lipids peroxidation. Therefore the natural or synthetic inhibitors may serve as detoxificating agents. The first experimental data showing the protective effect of vitamin E was presented early /54/, accompanying the proposition that free radicals derived from methylmercury compounds are responsible for oxidative stress.
Indeed, when enhanced lipid peroxidation in liver, kidney and brain of mice has been observed after exposure to CH3HgCI, the pre-treatment with diets containing c-tocopherol or [3-carotene produces protective effect /15/. High dietary a-tocopherol protected against CH.HgCI induced hepatic lipid peroxidation and increased the activity of total glutathione peroxidase and Se-dependent glutathione peroxidase inhibited by CH3HgCI in the kidneys. Natural antioxidants-vitamin E and ascorbic acid-may protect against in vivo toxic effects of mercury in the mammalian tissues/55,56/. The in vivo effectiveness of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, used as water soluble vitamin E analogantioxidant "Trolox", against the methylmercury-induced cellular responses was demonstrated/57/.
The addition of vitamin E (c-tocopherol) to the diet containing CH.HgNO3 demonstrates the inhibition of peroxidation level in rat liver homogenates /43/ (Table 4).
Organic Derivatives of Mercury and Tin as Prom.otet" ?f Membrane Lipid Peroxidation. Table 4 The impact of methylmercury iodide and vitamin E on the lipid peroxidation level in rat liver homogenates* The monitoring has been done by studying the enzymatic and non-enzymatic peroxidation levels. The detoxification effects of c-tocopherol on the enzymatic and non-enzymatic peroxidation level in vivo in fish samples (Stellate sturgeon, Russian sturgeon) were observed when tested fish were fed with methyl derivatives of Hg and Sn/58/. (Figs. 6,7). The experiments with model compoundoleic acid, as a representative of unsaturated fatty acids, proved the assumption of the preventive effect of antioxidants on the prooxidative function of organomercury ( Table  5,6) and organotin compounds (Fig. 8)/24,26/. Table 5 The kinetic data for the oxidation of oleic acid in the presence of mM organomercury compounds and mM antioxidants at 60C* Additives Without additives c-tocopherol t-tocopherol acetate 2,4,6-tri-tert-butylphenol 2,6-di-tert-butylphenol  Vol. 2, Nos. [1][2]2004 Organic Derivatives of Mercury and Tin as Promoters of Membrane Lipid Peroxidation These data make it possible to propose that the rates of radical substitution reactions at metal center are lower than the corresponding values of hydrogen abstraction by peroxyl radicals of substrates. Nevertheless the homolytic cleavage of carbon to metal bonds might play a significant role in the mechanism of organometallics action in the radical and oxidative bioprocesses.

CONCLUSION
The toxicity mechanisms of mercury and tin organic derivatives are still a matter for debate. The explanations of their biochemical mode of action are inconsistent. The organometallic compounds R,,MXm (M Hg, Sn) are broad-spectrum biocidal agents whose toxic effect is primarily manifested at the membrane level due to the lipophilic nature of their molecules. The ability of mercury and tin atoms to bind biologically important molecules through the interaction with heteroatoms of biosubstrates and to disturb mostly protein systems is well known. On the other hand the involvement of R,MXm in the biochemical reactions in which the organic moieties and carbon to metal bonds are responsible for the key processes is still purely investigated. However the dependence of the organometallics toxicity on the type and number of R groups in their molecules is clearly proved.
The data collected recently and presented here are fundamentally important to recognizing the difference between the role of metal centers and of organic fragments in the biochemical behavior of R,,MX,,, in their interaction with primary biological targets when entering a living organism and penetrating a cellular membrane. Toxic doses of organomercury and organotin compounds are capable of disturbing the natural oxidation/reduction balance in cells through various mechanisms stemming from their own complex radical and redox reactions with endogenous oxidants. The consequences of this action produce the effects on cellular antioxidant systems. The resulting oxidative stress may damage cellular membranes and membranedependent redox sensitive enzymatic systems. This, in turn, may produce a variety of toxic effects, including pathological processes that lead to cell death. Therefore there is a strong need to investigate in more depth the principal radical bioprocesses which involve the organometallic molecules. The understanding of the mechanistic mode of toxic action of may lead to new approaches for the utilization not only of chelating agents as antidotes against heavy metals compounds but of inhibitors and antioxidants as preventative additives for the detoxification of heavy metal organic derivatives.