l‐Methionine activates Nrf2‐ARE pathway to induce endogenous antioxidant activity for depressing ROS‐derived oxidative stress in growing rats

Abstract BACKGROUND Methionine is an essential sulfur‐containing amino acid. To elucidate the influence of l ‐methionine on activation of the nuclear factor erythroid 2‐related factor 2–antioxidant responsive element (Nrf2‐ARE) antioxidant pathway to stimulate the endogenous antioxidant activity for depressing reactive oxygen species (ROS)‐derived oxidative stress, male Wistar rats were orally administered l ‐methionine daily for 14 days. RESULTS With the intake of l ‐methionine, Nrf2 was activated by l ‐methionine through depressing Keap1 and Cul3, resulting in upregulation of ARE‐driven antioxidant expression (glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modulatory subunit, glutathione synthase (GS), catalase (CAT), superoxide dismutase (SOD), heme oxygenase 1, NAD(P)H:quinone oxidoreductase 1, glutathione reductase (GR), glutathione S ‐transferase (GST), glutathione peroxidase (GPx)) with increasing l ‐methionine availability. Upon activation of Nrf2, glutathione synthesis was increased through upregulated expression of methionine adenosyltransferase, S ‐adenosylhomocysteine hydrolase, cystathionine β‐synthase, cystathionine γ‐lyse, glutamate cysteine ligase (GCL) and GS, while hepatic expressions of methionine sulfoxide reductases (MsrA, MsrB2, MsrB3) and hepatic enzyme activities (CAT, SOD, GCL, GR, GST, GPx) were uniformly stimulated with increasing consumption of l ‐methionine. As a result, hepatic content of ROS and MDA were effectively reduced by l ‐methionine intake. CONCLUSION The present study demonstrates that methionine availability plays a critical role in activation of the Nrf2‐ARE pathway to induce an endogenous antioxidant response for depressing ROS‐derived oxidative stress, which is primarily attributed to the stimulation of methionine sulfoxide reductase expression and glutathione synthesis. © 2019 Society of Chemical Industry