The Proteasome Is a Molecular Target of Environmental Toxic Organotins

Abstract

BackgroundBecause of the vital importance of the proteasome pathway, chemicals affecting proteasome activity could disrupt essential cellular processes. Although the toxicity of organotins to both invertebrates and vertebrates is well known, the essential cellular target of organotins has not been well identified. We hypothesize that the proteasome is a molecular target of environmental toxic organotins.ObjectivesOur goal was to test the above hypothesis by investigating whether organotins could inhibit the activity of purified and cellular proteasomes and, if so, the involved molecular mechanisms and downstream events.ResultsWe found that some toxic organotins [e.g., triphenyltin (TPT)] can potently and preferentially inhibit the chymotrypsin-like activity of purified 20S proteasomes and human breast cancer cellular 26S proteasomes. Direct binding of tin atoms to cellular proteasomes is responsible for the observed irreversible inhibition. Inhibition of cellular proteasomes by TPT in several human cell lines results in the accumulation of ubiquitinated proteins and natural proteasome target proteins, accompanied by induction of cell death.ConclusionsThe proteasome is one of the molecular targets of environmental toxic organotins in human cells, and proteasome inhibition by organotins contributes to their cellular toxicity.

Molecular modeling for the interaction between proteasome beta 5 subunit and organotin compounds

“…In the environment, tributyltin (TBT) and triphenyltin (TPT) are more toxic than those with one, two, and four butyl/phenyl substitute organotins. Recently, we reported that the cellular proteasome is a molecular target of some organotins [12,13], and TBT and TPT possessed higher inhibitory potency to proteasomal chymotrypsin-like activity than other butyl/phenyl substitute organotins [12]. The purpose of the present study is to establish a mechanistic model that could describe how organotins interact with the active site of proteasome 5 subunit for understanding the role of the Sn atom in the binding of organotins to proteasome 5 subunit.…”

“…Purified human 20S proteasome (0.02 g) was incubated with 40 M of fluorogenic peptide substrates in 100 L assay buffer (20 mM Tris-HCl, pH 7.5) in the presence of organotins at different concentrations at 37 °C, followed by the measurement of proteasomal chymotrypsin-like activity [12].…”

“…We have found that both triphenyltin (TPT) and tributyltin (TBT) were potent inhibitors to the proteasome with IC 50 values of 3.5 mol/L and 15.6 mol/L, respectively [12].…”

Characterization of interactions between organotin compounds and human serum albumin by capillary electrophoresis coupled with inductively coupled plasma mass spectrometry

“…Organotin compounds could accumulate in livers and tissues, resulting in sex differentiation or other illnesses. Organotin compounds have already been considered as endocrine disruptors [30,31]. However, the mechanism for the interaction between organotin species with proteins and other biomolecules is not clear and still needs to be elucidated.…”

O desregulador endócrino, dibutilestanho, é um antagonista de PPAR-alfa em ensaios de gene repórter

“…Bax protein was also increased dose dependently after the treatment. This concludes that TBT can inhibit the proteasome and can activate the cell death associated proteins, while the DNA strand break has not observed with TBT or TPT [62].…”