Sulfite attenuates methylglyoxal-induced carbonyl stress by enhancing intracellular metabolism with glutathione and extracellular direct sequestration in SH-SY5Y cells.

Carbonyl stress caused by the accumulation of advanced glycation end products (AGEs) and excessive methylglyoxal production may be involved in the development of various neurodegenerative diseases. Sulfite is an endogenous intermediate of sulfur metabolism that protects against oxidative stress in neurons; however, the effect of sulfite on carbonyl stress in neuronal cells remains unclear. In this study, we examined the effects of sulfite on MGO-induced toxicity in human neuroblastoma SH-SY5Y cells. Pretreatment with sulfite attenuated MGO-induced cell death and suppressed the accumulation of MG-H1, which is a major MGO-derived AGE. These effects were accompanied by increased intracellular cysteine and glutathione levels and were abolished under cysteine/cystine-depleted conditions, which indicates that the enhancement of intracellular glutathione availability is the major intracellular mechanism underlying sulfite-mediated protection. In contrast, simultaneous treatment with sulfite suppressed MG-H1 formation, even in the absence of extracellular cysteine/cystine in SH-SY5Y cells. LC-MS/MS analysis revealed direct adduct formation between sulfite and MGO. These results indicate that sulfite modulates MGO-induced toxic responses in an in vitro neuronal cell model through glutathione-associated defense and direct extracellular sequestration of MGO.