Redox modulation as a mechanistic feature of biological effects of cysteine and glutathione mixed disulfide conjugates of Allium thiosulfinates

Abstract

The objective of this work was to determine if phase II enzyme induction and inhibition of nitric oxide (NO) evolution by cysteine and glutathione mixed disulfide conjugates of Allium thiosulfinates (CySSR/GSSR) were linked to redox homeostasis in cultured cells. The CySSR/GSSR species induced quinone reductase (QR) through the Nrf2 pathway in Hepa 1c1c7 cells, and inhibited iNOS expression and NO evolution in LPS‐activated macrophages. CySSR/GSSR also modulated intracellular redox status by boosting intracellular GSH levels. The effects of the CySSR and GSSR species were progressively attenuated by the addition of exogenous thiol agents that influenced redox status in a dose‐dependent manner in both intracellular and extracellular spaces. Thus, the biological activities of CySSR/GSSR appear to be dependent on both extracellular and intracellular redox status. The effects of CySSR, but not GSSR, treatments resulted in an increase in extracellular thiol levels. Evidence was obtained for a mechanism involving cellular uptake of CySSR by L transporter, disulfide bond reduction by thioredoxin reductase (TRxR) and the export of cysteine and RSH into the medium by multiple drug resistance protein. This study adds to the evidence that Allium organosulfur compounds and metabolic derivatives exert a range of biological effects through a redox‐modulatory mechansism.Supported by USDA‐NRI‐CGP.