Osaka Metropolitan College researchers investigated the modifications that happen within the livers of mice when aldehydes are quickly produced within the physique. Credit score: Osaka Metropolitan College
Researchers have recognized the mechanism by which a typical genetic mutation will increase liver illness danger. Their findings counsel that wholesome selections, corresponding to growing antioxidants and limiting publicity to smoke, could cut back the chance of this illness.
The examine was printed in Free Radical Biology and Drugs.
Aldehyde dehydrogenase 2 (ALDH2) is a vital enzyme that detoxifies dangerous aldehydes produced within the physique. Whereas it’s best recognized for metabolizing acetaldehyde—an aldehyde elevated by consuming—it additionally performs a job in detoxifying different dangerous aldehydes, together with acrolein.
Acrolein is a extremely reactive aldehyde produced by environmental publicity to pollution corresponding to cigarette smoke. It damages proteins, DNA, and lipids, contributing to heart problems, neurodegeneration, and different circumstances.
Some East Asians have a genetic mutation (ALDH2*2) that impairs the operate of ALDH2. It’s estimated that about 40% of Japanese individuals carry this mutation. The carriers of the mutation have an elevated danger of esophageal most cancers, particularly amongst heavy drinkers and people who smoke.
To know how acute liver harm happens in dwelling organisms when aldehyde detoxing is impaired, a analysis group led by Affiliate Professor Takeshi Izawa and graduate scholar Yuki Takami of the Graduate College of Veterinary Science, Osaka Metropolitan College, used knock-in mice.
These mice are bred to breed the dysfunction of the ALDH2 enzyme seen in human ALDH2*2 carriers, making them helpful for modeling the processes that result in liver illness in people and finding out the modifications that happen when aldehydes are quickly produced within the physique.
The researchers used allyl alcohol, an alcohol that’s metabolized into acrolein within the liver. They discovered that elevated ranges of acrolein coincided with the extent of a number of aldehydes quickly growing within the blood, a phenomenon they named an “aldehyde storm.”
This subsequently causes aldehydes to build up within the liver, inflicting extreme liver injury. Their mechanism suggests the injury that may be triggered in individuals after publicity to excessive ranges of acrolein, particularly in these with the ALDH2*2 gene variant.
“The exposure level of acrolein used in this study clearly exceeds that of smoking; therefore, the risk of severe liver damage like that reported in this paper occurring by smoking only is low,” Izawa mentioned.
“Instead, it is likely that the risk is higher in patients receiving anticancer drugs, such as cyclophosphamide, which is metabolized to acrolein in the body.”
Usually, acrolein is detoxified by the antioxidant glutathione; nonetheless, this didn’t occur within the mice. As an alternative, the researchers discovered that the degrees of glutathione within the liver had been severely depleted, indicating an inverse affiliation with the aldehyde storm.
Glutathione additionally suppresses oxidative stress and, accordingly, they discovered that the glutathione depletion promoted oxidative stress within the liver, resulting in ferroptosis, a kind of cell demise. The researchers discovered proof of tissue injury throughout organs, with the liver being essentially the most severely affected.
“We identified for the first time the close relationship among aldehyde metabolism, redox balance, and the ferroptosis pathway,” Takami mentioned.
Their findings might also be related to individuals who carry the ALDH2*2 gene variant. These individuals usually have a lowered capability to interrupt down aldehydes from alcohol, sure meals, and environmental chemical substances.
In these people, the liver’s antioxidant defenses could be overwhelmed by sudden will increase in aldehyde ranges, resulting in cell demise and extra extreme liver harm.
Their findings counsel that the aldehyde storm is a key a part of this course of. It additionally emphasizes the significance of individuals with this variant avoiding excessive aldehyde publicity, supporting their antioxidant system by means of a nutritious diet, and monitoring their liver well being.
“Acrolein is also found in electronic cigarette smoke and as a metabolite of anticancer drugs. The results of this study suggest that ALDH2*2 carriers may be at health risk from daily exposure to aldehydes caused by smoking and in certain medications,” Izawa mentioned.
“Going forward, we plan to investigate other health effects of chronic exposure to aldehydes in ALDH2*2 carriers, particularly their involvement in cancer.”
Extra info:
Yuki Takami et al, Systemic aldehyde storm induced by allyl alcohol publicity leads to in depth hepatic ferroptosis in Aldh2∗2 knock-in mice, Free Radical Biology and Drugs (2025). DOI: 10.1016/j.freeradbiomed.2025.07.045
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The ‘aldehyde storm’: How a gene mutation present in East Asian individuals will increase liver illness danger (2025, September 12)
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