Biological chemistry of organotin compounds: Interactions and dealkylation by dithiols

Abstract

In this paper, we review our past and current efforts toward the elucidation of the biological chemistry of organotin compounds. In particular, we cover two prominent aspects of organotin compounds: their reactivity toward biological dithiols, and their degradation (or metabolization) mechanism using a combination of experimental and computational techniques.

Introduction

Organotin compounds are amongst the most widely used organometallic compounds. Over the last several decades, they have been utilized for a variety of industrial and agricultural applications including pesticides, fungicides and anti-fouling agents [1]. Run-off from organotin compounds used for agriculture accounts for the largest source of organotin accumulation in the environment, and has increased concerns regarding their toxic effects toward living organisms. The adverse environmental effects of organotin compounds have surpassed their usefulness in day to day applications, prompting bans on compounds such as tributyltin chloride (TBT) in the Unites States during the late 1980s [2], [3]. While similar bans in developed nations have helped to decrease the overall incorporation of certain organotin compounds into the environment, several foreign countries still produce and utilize vast quantities of these compounds [2], [3].

Indeed, traces of trimethyltin salts (TMT), which have not been implemented in commercial applications due to their high level of toxicity, have been found in the urine of humans not exposed directly to TMT, reinforcing the concern of environmental contamination [4]. Accidental human exposure to TMT has resulted in the appearance of dramatic behavioral changes, including weakness, aggressive behavior, depression, disorientation, seizures, severe memory loss, and in some instances death [5], [6], [7], [8], [9]. A distinguishing feature of organotin toxicity is the high level of specificity these compounds exhibit toward their biological targets. For example, TBT and triphenyltin salts (TPT) are primarily immunotoxic, while triethyltin chloride (TET) and TMT exhibit neurotoxic activity. Furthermore, while TMT and TET are both neurotoxic, they behave differently, inducing selective damage to distinct regions of the central nervous system. TMT-induced toxicity is localized within the hippocampus and neocortex of the brain, while TET predominately affects regions of the spinal cord. The selective neurotoxic pattern of TMT has made it an ideal system for studying organotin effects [9], [10], and in general, the high specificity and toxicity of all organotin compounds have made them excellent candidates for modeling the mechanisms of alkylmetal intoxication in mammalians, though little attention has been focused on their biological chemistry under near physiological conditions.

Organotin toxicity is directly linked to the number and nature of the organic moiety. Highly substituted organotin compounds are known to be the most toxic (tri- and di-substituted organotins), with their toxicity decreasing with increasing alkyl chain length in a manner independent of the counter ions [11]. Among the most interesting properties of organotin compounds is their environmental degradation (speciation) by physico-chemical factors (UV, pH) and metabolization carried out by prokaryotic and eukaryotic organisms. In spite of its relatively high dissociation energy (∼190–220 kJ/mol), the covalent Sn–C bond can be cleaved by a number of environmental sources, including chemical attacks (nucleophilic or electrophilic), UV radiation, and dealkylation by bacteria [12]. In mammalian organs such as the brain, liver and kidneys, organotin compounds are systemically degraded to inorganic tin, with the extent of the dealkylation correlating inversely with the length and stability of the alkyl moiety [13]. This noted in vivo degradation may provide an explanation for the delayed toxic response to organotin compounds observed in mammals [14].

Given the important role of organotin compounds in pollution and toxicology, the literature concerning their binding to biological macromolecules is rather scarce. Most studies focus on organotin interactions with hemoglobin [15], [16], [17], [18], liver mitochondria [19], [20], [21], [22], [23] and ATPases [24] at a macroscopic level. It is only very recently that attention has been focused on the possible molecular mechanisms of organotin toxicity. One mechanism postulated for protein–organotin interactions is the formation of covalent bonds between the tin(IV) atom and thiols present in proteins [2], [17], [25]. This mechanism has been corroborated by recent in vitro studies showing that vicinal dithiols rather than monothiols are responsible for mediating the biochemical effects of organotin compounds [25], [26], [27], [28].

While the mediation of thiol groups seems to be a common theme in organotin–protein interactions, a more recent paper from Ballmoos et al. shows a different mechanism of interaction between TBT and F-ATP synthase [29]. According to these researchers, TBT interacts with the selectivity filter of the ion channel of subunit a of ATP synthase through non-covalent interactions without any explicit involvement of the thiols in the coordination of the tin atom. Moreover, a few papers have been published on the effects of di- and trialkyltin compounds on membrane stability [30], [31] and on their interactions with carbohydrates and DNA fragments in the solid state [32], [33], [34] and in solution [35], [36]. In particular, it has been observed that organotin compounds (i.e., TBT and TPT) do not modify the macroscopic organization of lipid bilayers; rather, they modify the degree of hydration by interacting preferentially with the lipid/water interface [30].

In the last few years, our laboratory has embarked on the characterization of the biological chemistry of the organotin compounds. Our final goal is to answer the following questions: What are the biological targets of organotin compounds? What is the physiological mechanism of their dealkylation? Which is the toxic species, the highly substituted organotins or their metabolic products? Not only will this knowledge make it possible to implement appropriate therapeutics for cases of accidental intoxication, but it will also be useful in the development of new bioremediation technologies. In this paper, we review our latest efforts to rationalize the mechanisms of interaction and degradation of organotin compounds with dithiols. We will begin by focusing on the experimental studies of interactions between organotin compounds and model peptides and then describe the mechanistic studies that we have carried out using computational methods.