Tea for Too Much Bilirubin?

A sip of tea or the glare of fluorescent light. Tradition versus technology. Those contrasting ideas reflect different ways to treat jaundice, one of the most common problems faced by newborns, especially premature infants. Yellowing of a baby’s skin and eyes often reveals the condition, which stems from too much bilirubin, a waste product created by the breakdown of hemoglobin molecules from red blood cells. The liver normally clears bilirubin from the body, but in newborns, the immature organ isn’t always up to the task.

Jaundice can be a serious problem since babies may suffer brain damage if bilirubin concentrations aren’t kept to safe levels. That’s why most U.S. and Europeans physicians turn to phototherapy, a strategy in which the baby spends hours under fluorescent lights. Light shining through the skin changes bilirubin molecules into a form more easily disposed of by the body.

In Asia, however, an herbal remedy called Yin Zhi Huang has for centuries been given to newborns to prevent or treat jaundice. The medicine is made by brewing a tea from a mixture of four plants, including Yin Chin (Artemisia capillaris), which in the West is known as wormwood.

David D. Moore of Baylor College of Medicine and his colleagues have now used the modern tools of molecular biology to confirm Yin Zhi Huang’s bilirubin-clearing proficiency and to figure out how the traditional herbal remedy works. In the Jan. 1 Journal of Clinical Investigation, they identify a chemical that stimulates bilirubin elimination in mice and is present in extracts of both Yin Zhi Huang and pure Yin Chin.

“This is a wonderful example of knowledge gained by applying Western scientific method to an Eastern herbal remedy. It will be very exciting if a pure compound emerges from the tea leaves as a pharmacological therapy for neonatal jaundice that is complementary or alternative to the current Western practice of phototherapy,” Mitchell A. Lazar of University of Pennsylvania school of Medicine writes in a commentary accompanying the new research.

Moore’s interest in Yin Zhi Huang evolved from his team’s efforts to characterize the role of certain proteins inside cells that turn on genes. Called nuclear receptors, these proteins are first triggered by molecules entering the cell and then latch on to specific DNA sequences. This turns on target genes. The best-studied nuclear receptors are activated by steroids and other hormones, but many of the almost 50 known nuclear receptors don’t respond to hormones, notes Moore.

It turns out that the triggers of these mysterious receptors are often components of a person’s diet or compounds generated by the metabolic breakdown of food. Take the nuclear receptor called constitutive androstane receptor, or CAR.

“We knew it was responsive to a lot of different things,” explains Moore. It’s fairly promiscuous. That’s because it controls the metabolism of drugs and other compounds. We also knew that it controls the metabolism of endogenous toxic products, including bilirubin.”

To explore CAR’s potential connection to the actions of Yin Zhi Huang, Moore and his colleagues intravenously administered bilirubin to normal mice and ones genetically engineered to lack the nuclear receptor. They then fed the animals an extract of either Yin Zhi Huang or pure Yin Chin. Both extracts lowered the amount of bilirubin in the normal mice but left bilirubin concentrations in the mutant mice largely unaffected, indicating that the herbs work through CAR.

The scientists then isolated from Yin Zhi Huang and Yin Chin a compound called 6,7-dimethylesculetin, which activates CAR in lab-grown human liver cells and in mice genetically engineered to have the human form of the nuclear receptor in their livers. When administered to mice, the compound speeds the clearance of bilirubin much as Yin Zhi Huang and Yin Chin do.

“We’re confident that [6,7-dimethylesculetin] can do the job all by itself,” says Moore. “We’re not sure it’s the only thing in [Yin Zhi Huang] that activates CAR. It’s certainly an active ingredient.”

Administered carefully, phototherapy is a safe and effective treatment for jaundice, so it’s not clear there’s a huge demand for a new pharmacological approach to the problem, Moore acknowledges. Still, phototherapy is bothersome to infants, whose eyes must be protected from the light. And people who have an inherited tendency toward poor bilirubin clearance throughout their lives might prefer pills to phototherapy. “I’ve been contacted by a number of drug companies who have some interest,” says Moore.

Moreover, the traditional use of Yin Zhi Huang may be just one chapter in the story of dietary substances that interact with powerful nuclear receptors. “We’re interested in the prospect that there are other herbal medicines and natural products that may target these receptors,” says Moore.