Antioxidant properties of S-adenosyl-L-methionine in Fe²⁺- initiated oxidations

S-Adenosylmethionine (SAM) is protective against a variety of toxic agents that promote oxidative stress. One mechanism for this protective effect of SAM is increased synthesis of glutathione. We evaluated whether SAM is protective via possible antioxidant-like activities. Aerobic Hepes-buffered solutions of Fe²⁺ spontaneously oxidize and consume O₂ with concomitant production of reactive oxygen species and oxidation of substrates to radical products, e.g., ethanol to hydroxyethyl radical. SAM inhibited this oxidation of ethanol and inhibited aerobic Fe²⁺ oxidation and consumption of O₂. SAM did not regenerate Fe²⁺ from Fe³⁺ and was not consumed after incubation with Fe²⁺. SAM less effectively inhibited aerobic Fe²⁺ oxidation in the presence of competing chelating agents such as EDTA, citrate, and ADP. The effects of SAM were mimicked by S-adenosylhomocysteine, but not by methionine or methylthioadenosine. SAM did not inhibit Fe²⁺ oxidation by H ₂O₂ and was a relatively poor inhibitor of the Fenton reaction. Lipid peroxidation initiated by Fe²⁺ in liposomes was associated with Fe²⁺ oxidation; these two processes were inhibited by SAM. However, SAM did not show significant peroxyl radical scavenging activity. SAM also inhibited the nonenzymatic lipid peroxidation initiated by Fe ²⁺ + ascorbate in rat liver microsomes. These results suggest that SAM inhibits alcohol and lipid oxidation mainly by Fe²⁺ chelation and inhibition of Fe²⁺ autoxidation. This could represent an important mechanism by which SAM exerts cellular protective actions and reduces oxidative stress in biological systems.