Scientists from the University of Chicago Medical Center have found molecular evidence that bioflavonoids, which are ordinarily considered quite beneficial, can cause breaks in DNA that could trigger the development of infant leukemias. Bioflavonoids are found at high levels in many foods, including soybeans, fruits, root vegetables and herbs, and are often ingested in high concentrations as dietary supplements.
The researchers found that 10 out of the 20 bioflavonoids tested caused breaks in one small region of a gene known as MLL, which is a key player in about 80 percent of infant leukemias. Some bioflavonoids were as active in causing DNA damage as the powerful anti-cancer drug etoposide (VP16), which has been tied to secondary leukemias -- cancers of the bone marrow that result from previous anti-cancer therapy.
"Although bioflavonoids may be beneficial in certain circumstances, our studies suggest that high dietary intake of bioflavonoids could cause DNA breaks in MLL and possibly in other partner genes," note the authors in the April 11 issue of the Proceedings of the National Academy of Sciences.
The DNA damage seen after exposure to either bioflavonoids or to anti-cancer drugs VP16 or doxorubicin (Dox) was identical, affecting one small region of the MLL gene. Although most adult leukemias involving MLL affect a different part of the gene, the breakpoints found in infant leukemias and secondary leukemias occur predominantly in the small region altered by the bioflavonoids.
"This strongly supports the notion that bioflavonoids could be a causative agent for infant and possibly childhood leukemias," continue the authors. "Maternal ingestion of bioflavonoids may induce MLL breaks and potentially translocation in utero," they conclude, "leading to infant and early childhood leukemias."
Infant leukemias are rare, affecting only about 37 out of every million children in the United States. Some researchers have argued that the cause may be an infectious agent, but epidemiologic studies have suggested that maternal consumption of foods such as bioflavonoids could lead to an increased risk of infant leukemia. A 1988 study found the disease to be nearly twice as common in several large Asian cities, where soy intake is two to five times as high as in the U.S.
The researchers, using blood and bone marrow cells from healthy newborns and adults, as well as leukemic cell lines, were able to determine the mechanism of DNA damage. The bioflavonoids, like the drugs VP16 and Dox, inhibit the action of an enzyme known as topoisomerase II (topo II), which helps to cleave apart and then rejoin strands of DNA, a process that is pivotal for various cell functions.
Leukemia can result when these normal DNA breaks are not properly reconnected, part of topo-II's mission.
MLL is a promiscuous gene. Once broken, it can reconnect with any of more than 40 other genes in a translocation, a process that involves an exchange of DNA between two chromosomes. Extensive recombinations usually cause cell death; but subtle translocations involving MLL can result in the rapid, uncontrolled cell division seen in leukemia.
Interestingly, cancerous cell lines that had developed resistance to drugs like VP16 and Dox were not susceptible to bioflavonoid DNA breaks.
Certain types of bioflavonoids, especially the flavonols, were more powerful topo-II inhibitors than others. For example, two different forms of quercetin, a dietary supplement, and fisetin, which is derived from herbs, were equal to VP16 in triggering MLL cleavage. Combinations of these substances demonstrated a cumulative effect.
Another group, the flavanones, found in citrus fruits, did not induce MLL cleavage.
"The public health message from this study is not yet clear," said Janet Rowley, M.D., Blum-Reise Distinguished Service Professor in the departments of medicine, molecular genetics & cell biology, and human genetics at the University of Chicago and director of the study.
"The health benefits of a diet high in foods containing bioflavonoids, such as soybeans, citrus fruits and root vegetables is unquestioned. The probable benefits of bioflavonoids themselves have also been demonstrated, such as the low mortality rates from prostate cancer in Asian men compared to Western countries, which may be because of higher intake of isoflavones."
The benefits of dietary supplements containing bioflavonoids, however, may not be so convincing. This study suggests that pregnant women, at least, should be especially careful about taking such supplements or even eating a diet high in bioflavonoids.
Additional authors of the study include Reiner Strick, Pamela Strissel, Susanne Borgers and Steve Smith, all of the University of Chicago. This work was supported by the National Cancer Institute and the G. Harold and Leila Mathers Charitable Foundation.
Journal
Proceedings of the National Academy of Sciences