Liver: New Regulator of Drug Detoxification Discovered

10/14/2013
Photo: Liver damage

The protein FRA-1 neutralizes the damage caused by different agents to the liver; © panthermedia.net/
Sebastian Kaulitzki

A CNIO group led by researcher Erwin Wagner discovered that the Fra-1 protein is causally involved in liver fibrosis and protects the liver from drug-induced liver damage.

Drug abuse and alcohol are some of the most frequent causes of liver damage, particularly in developed countries. Such kind of liver damage can cause irreversible liver failure and even cancer. Researchers from the Spanish National Cancer Research Centre (CNIO) have discovered an important new protective role of the Fra-1 protein, which neutralizes the damage caused by agents, such as the analgesic drug acetaminophen (Paracetamol). This is the first study to reveal a function of Fra-1 in protecting this important organ.

Key to the study has been a new 'super-detoxifying' mouse model generated by the team around Erwin Wagner, Director of the BBVA Foundation-CNIO Cancer Cell Biology Programme. "Our mouse was designed to produce extra Fra-1 protein only in the liver, which allowed us to study its specific function in this organ and thus eliminate side effects that an excess of protein might have in other tissues", explains Sebastian Hasenfuss, first author of the study.

Increased production of Fra-1 in the liver of these mice protects the organ from damage caused by drugs, such as Paracetamol. Moreover, Wagner's team also found that the removal of Fra-1 in mice causes a significant increase in liver damage. How Fra-1 protects the liver is another question that Wagner's team answers. On one hand, Fra-1 stimulates genes related to the glutathione defense system against free radicals and thus avoids cellular damage. On the other hand, Fra-1 stimulates genes that cause the removal of toxins from the body.

These results bring to light a new molecular component that could be key in future studies searching for new drugs for diseases related to the accumulation of toxic compounds, such as acute liver disease, alcoholism or cancer.

The team also highlights the importance that Fra-1's detoxifying role might have in the generation of chemotherapy resistance: "Tumor cells use very similar mechanisms as Fra-1 to eliminate chemotherapeutic agents", says Wagner, concluding that: "This makes us think that tumors might use Fra-1 to generate chemotherapy resistance and thus be able to keep growing."

MEDICA.de; Source: Centro Nacional de Investigaciones Oncologicas (CNIO)