Scientists discover the mechanism for ethyl carbamate-induced toxicity in fermented food
Ethyl carbamate (EC) is a hazardous substance naturally produced during the fermentation of food and beverages. It has been categorized as probably carcinogenic to humans (Group 2A) by the World Health Organization's International Agency for Research on Cancer (IARC).
However, fermented food, such as kimchi, fermented tofu, yellow wine and brandy, is very popular among consumers for its distinctive flavor, and its sale is on the increase globally. Nonetheless, the health risk of EC cannot be ignored. Research indicates that the liver is one of EC's target organs, but the specific toxic effects remain obscure. Therefore, it is of supreme importance to conduct in-depth research into the toxicity mechanism of EC for the safety of fermented food.
Recently, the research team led by Prof. Chen Wei at the Zhejiang University College of Biosystems Engineering and Food Science published an article entitled "Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation" in the journal Redox Biology.
Ferroptosis is a newly identified ROS-mediated non-apoptotic cell death characterized by iron accumulation and excessive lipid oxidation. The researchers found that EC triggered ferroptosis in liver cells by detection of decreased cell viability, GSH, GPX4 and Ferritin levels, as well as increased iron and MDA contents. Ferroptosis inhibitor ferrostatin-1 (Fer-1) pretreatment rescued ferroptotic damage, indicating that ferroptosis was critical for EC-caused cell death.
Furthermore, GSH synthesis precursor N-acetylcysteine displayed significant anti-ferroptotic properties and Chen Wei et al. suggested that GSH depletion might be the primary cause of ferroptosis under EC exposure. EC-triggered GSH depletion depended on suppressed GSH synthesis via inhibition of SLC7A11 and GCLC expressions. Notably, EC blocked Nrf2 activation by repressing phosphorylation modification and nuclear translocation, which further resulted in ferroptosis occurrence. Prof. Chen and his colleagues also observed EC-induced liver dysfunction and inflammation, accompanied by oxidative stress, ferroptosis and downregulated Nrf2 signaling in Balb/c mice, which could be effectively reversed by Fer-1 and tBHQ pretreatment.
This study indicates that ferroptosis is a new mechanism for EC-caused toxicity due to Nrf2 inactivation and GSH depletion. It thus opens up a new avenue for the prevention and control of EC-induced oxidative damage, which will help ensure the safety of fermented food.
More information: Yang Xu et al, Ethyl carbamate triggers ferroptosis in liver through inhibiting GSH synthesis and suppressing Nrf2 activation, Redox Biology (2022). DOI: 10.1016/j.redox.2022.102349
Provided by Zhejiang University