Glutathione Drug Detoxification

Glutathione is the major intracellular thiol tripeptide found in all animal tissues, plants, fungi and some microorganisms. Under physiological conditions, it exists mainly in the cytoplasm in its reduced form (GSH), which is also the biologically active form. GSH concentrations in human cells are usually between 0.1 and 10 mmol/L, most concentrated in the liver (up to 10 mmol/L), spleen, kidney, lens, red and white blood cells, where its depletion or alteration is associated with various diseases, Including cancer, cardiovascular disease, inflammation, immune, metabolic and neurodegenerative diseases.

GSH is an essential component of the system, detoxifying electrophilic xenobiotics and metabolically generated free radicals, namely reactive oxygen species (ROS), through the formation of GSH S-conjugates. Therefore, it plays a central role in protecting cells from various exogenous and endogenous potentially harmful compounds. Thus, the effectiveness of the detoxification pathway depends on the intracellular concentration of GSH, the presence of GST with appropriate specificity, or the ability of cells to rapidly resynthesize GSH.

It is generally accepted that GSH conjugation of xenobiotics and conversion of thioethers to sulfhydryl acids is an organism's biochemical defense against potentially harmful compounds. Often, many substances lose their toxicity completely or partially due to the detoxification process.

The importance of GSH binding in drug detoxification depends on the extent to which it is metabolized to reactive intermediates. The reaction can be non-enzymatic (i.e. chemical) or enzymatic, with GST playing the biggest role.

To handle a wide variety of potential substrates, a variety of GSTs exist. In humans, liver cytosolic GST activity levels are highest, followed by kidney, lung, and intestine. There are many reports that structurally diverse anticancer drugs form GSH S-conjugates through a process catalyzed by GST, which are then degraded and removed from the body.

In recent years, this targeted covalent modification of regulatory proteins by Michael receptors has been recognized as a promising approach for drug discovery. GSH plays an integral role in the clearance of these electrophiles.