Each year, about 120,000 babies in the United States are born with birth defects, according to the March of Dimes — and about 3,000 of them suffer from metabolic disorders that, while not readily visible, may threaten their lives.
City of Hope scientist Wendong Huang, Ph.D., is shedding light on one such important metabolic defect involving constitutive androstane receptor, or CAR. An assistant professor in the Department of Gene Regulation & Drug Discovery, Huang recently was awarded the Basil O’Connor Starter Scholar Research Award by the March of Dimes for his continuing research into CAR. The $150,000 grant supports Huang’s research for two years.
Huang helped establish the regulatory role CAR plays in the liver.
As he explained, the human body processes medications in the liver, which breaks drugs down into smaller and less toxic compounds. Studies have shown that CAR is responsible for regulating drug metabolism in the liver, switching on and off when needed. However, when CAR is continuously activated, it changes how drugs are metabolized, which can cause liver damage, liver failure and even death.
“At some point in the early developmental stage of a fetus, even possibly during the embryonic stage, CAR is turned on by the mother’s exposure to chemicals that activate the receptor,” said Huang. “That activation appears to cause permanent imprinting of various liver genes, which then are no longer regulated. It is a potential defect that impacts liver function and toxicity.”
Huang’s research involving common medications has shown CAR’s significance. Acetaminophen, for example, is a frequently used over-the-counter painkiller that ordinarily is safe at recommended dosages, but can damage the liver at high dosages. In a previous study, Huang discovered that when CAR is in active mode, the liver’s ability to metabolize acetaminophen changes so that even normal doses of the drug can lead to serious liver damage.
“The defect changes how effective a drug may be and how toxic it may be to the system,” said Huang. “New drugs may need to be tested for possible interactions with CAR to ensure the medicines are safe.”
Many compounds activate CAR. In his experiments, Huang used phenobarbitol, a product prescribed to treat seizures in pregnant women, and TCPOBOP, which can be found in many herbicides and pesticides, as CAR activators. In his continuing studies under the Basil O’Connor Award, Huang hopes to discover how developmental imprinting occurs on the molecular level and further his research into its impact on liver metabolism and toxicity.
“The genetic sequence does not change with imprinting, and we think that CAR-mediated effects reflect epigenetic modification,” said Huang. “If we understand how imprinting occurs, we can work on finding ways to overcome it.”
The March of Dimes Basil O’Connor Award supports promising young scientists just embarking on their independent research careers. O’Connor was the former law partner of President Franklin D. Roosevelt and helped Roosevelt establish The National Foundation for Infantile Paralysis (later renamed the March of Dimes) in 1938, during an era of worsening polio epidemics in the United States. O’Connor led the foundation, guiding it to fund a wide variety of research in virology and genetic sciences.
In 1955, the foundation announced the safety and effectiveness of the polio vaccine developed by its grantee Jonas Salk, M.D. Today, the March of Dimes funds innovative programs of research, community services, education and advocacy to save babies from birth defects, premature birth and other leading causes of infant death and disability.