Glutathione in its reduced form, GSH, is on the forefront of a cell’s defense against oxidative stress damage including reactive oxygen species (ROS) formation. GSH is a peptide containing three amino acids (glutamic acid, glycine, cysteine) with the complete chemically correct name of:
g-L-Glutamyl-L-cysteinylglycine (2S)-2-amino-5-[(2R)-1-(carboxymethylamino)-1-oxo-3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid. GSH is ubiquitous in living cells.
As with just about everything else, a little bit of oxidative stress is good (it’s used for signaling pathways) whereas “too much of a good thing can be bad” for survival of the cell. A few weeks back –– during our email-chat of the Linear-No-Threshold (LNT) Model vs the model that “some quantifiable threshold exists for everything” (e.g. even gamma-irradiation has a threshold before it becomes damaging) –– some of us tried to think of a single chemical that might follow LNT modeling. I had suggested organic metals such as methyl-mercury (MeHg), i.e. could we detect/quantify toxicity for even a single molecule of MeHg in the cell?
That discussion brings us to the attached article. GSH pathways play a pivotal role in MeHg metabolism and elimination –– largely due to formation of a readily transported MeHg-GSH conjugate. Glutathione S-transferase (GST) enzymes have therefore been proposed to facilitate MeHg elimination by catalyzing MeHg-GSH conjugation. A role for the human GSTP1 enzyme in MeHg disposition had been suggested by the association of two common polymorphisms in the coding region (Ile105Val and Ala114Val) with Hg levels found in either blood or hair.
In the present study, authors investigated a functional role for GSTs in modulating MeHg toxicity during development. Using the fruit fly (Drosophila) model to execute targeted manipulations of both endogenous GSTs and the introduction of the human GSTP1 gene variants, authors were able to correlate gene and protein expression levels with GST activity and also with MeHg body burden and developmental outcome of the flies. RNA-interference (RNAi) knockdown of the fly’s endogenous GSTD1, GSTE1, or GSTS1 –– individually –– increased susceptibility to MeHg during pupal development resulted in a decreased rate of adult eclosion.
Exogenous expression of human GSTP1 in developing flies resulted in increased MeHg tolerance, compared with control flies as seen with elevated eclosion rates when reared on MeHg-containing food. Moreover, the GSTP1_105 and GSTP1_114 variants showed a diminished enzyme activity relative to wild-type GSTP1 activity. Authors also observed a trend –– whereby Hg body burden was inversely related to GST activity levels. However, in some instances, GSTP1 expression resulted in increased eclosion rates without lowering Hg body burden, suggesting that GSTs interact with MeHg by way of both toxicokinetic (absorption/distribution/metabolism/excretion) and toxicodynamic (downstream targets) mechanisms.
These intriguing findings indicate that GSTs moderate MeHg toxicity during development in this Drosophila experimental model sustem. Because both glutathione transferases and GSH appear to be abundant in every living cell, these findings are not consistent with the LNT Model for organo-mercury compounds.
Toxicol Sci April 2o17; 157: 211–221