What’s behind benzodiazepines’ side effects? VCU may have the answer

RICHMOND, Va. (WRIC) -- Although benzodiazepines like Valium and Xanas are often prescribed to treat mental health issues and inflammation-related diseases, Virginia Commonwealth University (VCU) researchers are investigating an important question: what is responsible for their long-term side effects -- particularly those linked to inflammation?

A research team from VCU and Columbia University in New York believes it to be protein-related, as per their findings published in March in The Proceedings of the National Academy of Sciences, since benzodiazepines may increase the risk of developing or worsening an inflammatory condition.

Their research further examined new ways to treat inflammation-related conditions, including certain cancers, arthritis, Alzheimer’s disease and multiple sclerosis.

“Numerous attempts have been made to determine the structure and elucidate the function of this mysterious membrane protein family,” said Youzhong Guo, Ph.D., an associate professor in the VCU School of Pharmacy’s Department of Medicinal Chemistry and one of the lead researchers of the new study. “Now, after decades of research, we finally have promising evidence that resolves some of the mysteries around this protein and could be crucial for advancing benzodiazepine drug design.” 

These drugs can be effective as a short-term treatment, but researchers are uncovering that "long-term use of the medication may influence inflammation levels in our bodies," according to a press release from Monday, April 14.

Benzodiazepines are extremely therapeutic, but they are also linked to human mitochondrial tryptophan-rich sensory proteins (HsTSPO1), which are connected to several diseases, including Alzheimer’s. Researchers believe this protein, located on the outer membrane of mitochondria in cells, is involved in certain side effects of the drugs.

“Tryptophan-rich sensory proteins like HsTSPO1 are found in all forms of life, from bacteria and plants to animals and humans,” Guo, who also serves as research faculty at the VCU Center for Drug Discovery, said. “We know that this type of protein functions as enzymes in bacteria, and when you consider evolutionary theory, the same type of protein is likely to be an enzyme in humans as well.” 

The structure of this particular protein has been a mystery to Guo and other researchers for a while due to the methods used to analyze what they call "membrane proteins." They said that "researchers use detergents to extract and stabilize these proteins," and those detergents can disrupt important lipid-protein interactions, making the proteins unstable and unable to function.

They found that the protein actually acts as an enzyme that breaks down a compound to produce bilindigin, which helps control oxygen species, known as "ROS" -- unstable molecules that can trigger inflammation and damage cells if not properly regulated.

Researchers said that this could explain how these medications cause side effects over time, "though more research is needed to fully understand whether these molecular mechanisms play a part in driving adverse side effects."

“Protein instability caused by detergents had thwarted our previous efforts to fully characterize its structure and function,” Guo said. “However, in our analysis, we found that HsTSPO1 performed its function when cholesterol was present, demonstrating how crucial it is to study this protein in an environment that is similar to its natural habitat. Similar to if you take a fish out of the water, it’s still a fish, but it will behave very differently.”