N-Acetyl-Cysteine supplementation lowers high homocysteine plasma levels and increases Glutathione synthesis in the trans-sulfuration pathway

Beneficial effects on several cardiovascular and neurodegenerative diseases

Glutathione (GSH), a compound derived of a combination of three amino acids - cysteine, glycine and glutamine - is the final product of homocysteine (Hcy) metabolism in the transsulfuration pathway. The major determinants of GSH synthesis are the availability of cysteine and the activity of the rate-limiting enzyme, glutamate cysteine ligase (GCL). A deficiency in transsulfuration pathway leads to excessive Hcy production (HHcy) and reduced GSH synthesis. This tripeptide, that exists in the reduced or active form (GSH) and oxidized variant (GSH), is the main antioxidant of the body. Independently of its antioxidant function, the compound has an anti-inflammatory role too, reducing the production of interleukines and the expression of TNF-alfa and iNOS synthase. A dysregulation of GSH synthesis is recognized as contributing factor to the pathogenesis of many pathological conditions. But, the insufficiency of the transsulfuration pathway is also responsible of HHcy. Besides, this condition decreases the activity of cellular gluthatione peroxidase, an intracellular antioxidant enzyme that reduces hydrogen peroxide to water with the prevalence of GSSH on GSH. The consequent GSH/GSSH impaired ratio also causes some common cardiovascular and neurodegenerative disorders. In both occurrences, N-Acetyl-Cysteine (NAC) supplementation supplies the cysteine necessary for GSH synthesis and contemporarily reduces HHcy, improving the GPx1 activity and further reducing oxidative stress.