BPB Reports

Paper Details

BPB Reports
Vol. 5 No. 1 p.5-8 2022
Selenium Toxicity Accelerated by Out-of-Control Response of Nrf2-xCT Pathway
  • Koji Ueda (Faculty of Pharmacy, Meijo University)
Koji Ueda , Yoshinori Okamoto , Akira Aoki , Hideto Jinno
Faculty of Pharmacy, Meijo University
Received: December 14, 2021;   Accepted: January 07, 2022;   Released: January 20, 2022
Keywords: selenium toxicity, Nrf2, xCT, selenite

Selenium (Se) is an essential biological element and selenite is used to supplement malnutrition of Se and may also have anticancer activity. However, Se is also known as a delicate micronutrient with a narrow window of useful dose and the mechanisms for the sudden toxic effect remain unclear. Recently, we reported elsewhere that selenite was incorporated into cells via xCT, a cystine/glutamate antiporter. xCT is regulated by a stress responsive nuclear factor erythroid 2-related factor 2 (Nrf2). Therefore, we hypothesized and preliminary substantiated that the Nrf2-xCT pathway underlies the toxicity mechanism of Se. Expression of xCT mRNA was remarkably increased in MCF-7 cells after Se treatment, which may further increase Se uptake and oxidative stress. Pretreatment with xCT or Nrf2 inhibitors prevented morphological changes by releasing cells from uncontrolled feedback on Se uptake. Paradoxically, Se-induced oxidative toxicity is promoted by a runaway of stress response in Nrf2-xCT pathway. The results imply a novel mechanism by which Se accelerates its oxidative toxicity through feedback via Nrf2-xCT. This mechanism explain the elusive toxicological properties of inorganic Se, including strong cytotoxicity, high sensitivity in cancer cells, and narrowness of pharmacological dose range.