A team of American scientists have worked on mice a new way to combat alcohol dependence – to block the enzyme aldehyde dehydrogenase selectively in the liver. This method avoids many side effects of standard alcohol therapy. In addition, it leaves the body tolerant to small doses of alcohol. In humans, this method could allow drinking wine or beer but would prohibit patients from drinking stronger drinks.
Two enzymes are responsible for removing alcohol from the blood in the human body. The first – alcohol dehydrogenase – turns it into acetic aldehyde, and the second – aldehyde dehydrogenase-2 (ADH) – finally breaks it down to acetic acid. If the aldehyde is not destroyed in time, it accumulates in tissues, including the brain and liver, and causes many unpleasant effects, such as nausea, pain, and heart rhythm disturbances. This happens not only with alcohol abuse but also as a result of congenital mutations in the ADH-2 gene, which occur in about 8% of people.
Modern drugs that are used to treat alcohol dependence, mimic the state of people who carry the mutation. They block the work of ADG-2 and cause discomfort when a person drinks alcohol. At the same time, ADH-2 has another function inside the cells: it neutralizes toxic aldehydes, which are formed during oxidative stress. Therefore, blocking drugs have many side effects, and doctors are looking for new ways to intervene in ADH.
A team of scientists from the under the direction of Bin Gao suggested selectively turning off ADH in different tissues. To test as much as possible, they created a series of knockout mice: with the ADH genes turned off in the liver, spleen, intestines, adipose tissue, or throughout the body.
These animals were drunk with alcohol and after a while, the concentration of aldehyde in the blood was measured. It turned out that in those mice in which ADH did not work only in the liver, the aldehyde accumulated four times less than those who were completely deprived of it, but twice as much as those who had it turned off in others tissues. This suggests that the liver plays the most significant role in the neutralization of aldehyde, but other organs are also involved in this process.
The researchers then compared the body’s response to alcohol in mice lacking the ADH gene completely or only in liver cells. They found that in both cases, after drinking alcohol in the liver, the work of genes that are associated with the inflammatory response is triggered. However, in those animals in which the gene was turned off only in the liver, traces of organ damage – for example, the enzyme alanine aminotransferase (ALT) – turned out to be less in the blood.
Scientists have suggested that mice with partially-turned off ADH will, like mice with completely turned off ADH, refuse large doses of alcohol, but may remain tolerant to small doses. To test this, they conducted a test with two bottles: the mice were offered the choice between ordinary drinking water and gradually increasing concentrations of alcohol.
Ordinary mice preferred alcohol, starting with a fortress of 3 degrees, then drank it more and more, and after 9 degrees they gradually reduced the dose, and the 21-degree drink, as a result, amounted to only a quarter of the total liquid consumed. Mice with a lack of ADH stopped drinking after 3 degrees and then did not choose alcohol, regardless of strength. But animals with partially turned off ADH – only in the liver – calmly tolerated weak drinks, and only after 9 degrees did they begin to give up stronger alcohol.
Then the authors of the work tried to selectively turn off the ADH in the liver in ordinary mice. To do this, they introduced an adenoviral vector with small interfering RNA into their bodies. The vector, according to the scientists, was to selectively deliver RNA to the liver cells, and it was already to contact the RNA protein ADH and start its destruction. Such animals stopped drinking alcohol after 6 degrees of the fortress. The therapy also worked when it was administered later – mice that are already accustomed to alcohol of a certain strength – under the influence of the viral vector, they began to lower the degree.
Based on their work, the researchers proposed a new way to combat alcohol addiction. Partial blockade of ADH causes the body enough trouble so that it does not seek to absorb alcohol of high strength, but in small doses – comparable to the strength of beer or wine – alcohol remains safe. Methods for turning off ADH in humans have, of course, to be worked out. However, a similar drug has recently been approved in the United States – it also acts on the basis of RNA interference and selectively enters the liver – and this means that such therapy is theoretically possible.