Journal News

Estrogen receptor antagonist shows promise for treatment of gallstone disease

Women are twice as likely as men to suffer from gallstone disease, due to estrogen’s role in triggering cholesterol gallstone formation. While small gallstones are common, in some people cholesterol forms crystals that build up and become too large for the gallbladder to expel. The resulting gallstone disease causes excruciating pain and sometimes sepsis. The standard treatment is surgical removal of the entire organ.

Christopher Arnatt, a researcher in the department of chemistry at St. Louis University, has been working to address the role of estrogen in gallstone disease. “Having a preventative cure out there for all at-risk people would be amazing,” he said.

Arnatt’s lab collaborated with David Q.H. Wang’s lab at the Marion Bessin Liver Research Center at the Albert Einstein College of Medicine in New York on a recent paper published in the Journal of Lipid Research.

Arnatt’s lab, which specializes in synthesizing compounds that target G protein–coupled receptors, created an array of drugs and tested their affinity for the G protein–coupled estrogen receptor, or GPER, which previously had been associated with gallstone formation.

“It took almost four years to nail down how to test for whether these compounds were binding to and antagonizing the G–coupled estrogen receptor,” Arnatt said. “No one had done any true medical chemistry on this, and now we have over one hundred compounds that bind to this receptor that can be used to study it further.”

Arnatt’s team showed that one of those compounds, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline — referred to as CIMBA — was selective for GPER, making it a strong candidate for further testing.

The second phase of the project put CIMBA to the test in mice. Wang’s lab, one of very few labs in the world that research gallstones, put ovariectomized female mice on a high-cholesterol diet and gave them doses of estradiol to induce gallstone formation. After eight weeks, the mice were injected with various doses of CIMBA, and then researchers removed their gallbladders.

These gallbladders, each about the size of a grain of rice, had to be cut open under a microscope to count and analyze their gallstones. Wang’s lab found that treatment with CIMBA reduced the formation of estrogen-induced gallstones in some mice and also found a dosage at which no gallstones formed. While the mouse model results are promising, making this compound available for human use would require safety testing and clinical trials. 

Arnatt is optimistic about the potential of CIMBA and the other GPER antagonists. “These new compounds will provide researchers with a lot of new tools,” he said. “Having new drugs out there will expand people’s ability to test this receptor and its pharmacology.”

Arnatt plans to investigate how to make CIMBA more bioavailable and less toxic for gallstone prevention treatment, and he hopes to use these GPER-binding compounds to understand better the receptor’s role in the body.

JLR-gallstones-890x664.jpg
Christopher Arnatt
G protein-coupled estrogen receptor with new selective antagonist, CIMBA, bound reduces estrogen-induced gallstones (background image) in female mice.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Guananí Gómez–Van Cortright

Guananí Gómez–Van Cortright is a teacher and freelance science writer.

Related articles

From the journals: JLR
Preeti Karwal
From the journals: JLR
Sephra Rampersad
From the journals: JLR
Poornima Sankar
From the journals: JLR
Swarnali Roy
From genes to hope
Nipuna Weerasinghe
From the journals: JLR
Laura Elyse McCormick

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Scientists track 'doubling' in origin of cancer cells
News

Scientists track 'doubling' in origin of cancer cells

June 15, 2024

Researchers at Johns Hopkins say they have charted a molecular pathway that can lure cells down a hazardous path of duplicating their genome too many times.

From the journals: JBC
Journal News

From the journals: JBC

June 14, 2024

Ribosomal RNA, R-loops and the RNA exosome. Using an old drug to treat a new skin disease, Sugar-binding immune receptors. Read about recent papers on these topics.

New gene new strides in gangliosidosis
Journal News

New gene new strides in gangliosidosis

June 11, 2024

A gene that decreases disease progression in mice provides a new direction for human therapy.

Brushing with bacteria: The debate over a GMO tooth microbe
News

Brushing with bacteria: The debate over a GMO tooth microbe

June 9, 2024

One startup has said a genetically modified microbe could prevent cavities. Experts, though, have safety concerns.

Newly discovered genetic variant clarifies why Parkinson’s develops
News

Newly discovered genetic variant clarifies why Parkinson’s develops

June 8, 2024

Researchers at the University of Florida have found that the mutation called RAB32 Ser71Arg both causes the condition and could show how to halt it.

From the journals: JLR
Journal News

From the journals: JLR

June 7, 2024

Switching cancer cells from pro- to antitumor. Species-specific skeletal muscle metabolism. Protein deletion improves metabolic disorders Read about recent papers on these topics.