Chinese herbal medicines containing aristolochic acids and their derivatives (collectively known as AAs) are widely implicated in hepatocellular carcinoma (HCC) in Taiwan and throughout Asia, a new study shows.
Mutational analysis of 98 HCCs from two hospitals in Taiwan revealed the distinctive mutational signature of AA exposure in more than three quarters (78%) of cases, “accounting for most of the nonsilent mutations in known cancer driver genes,” the study team found.
“This study shows that AA is involved in a remarkable proportion of liver cancers in Asia,” lead researcher Steven G. Rozen, PhD, director, Center for Computational Biology, and professor, Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School in Singapore, told Medscape Medical News.
The researchers also searched for the AA signature in 1400 HCCs from diverse geographic regions. Consistent with AA exposure through known herbal medicines, 47% of HCCs in Chinese patients showed the signature, albeit with lower mutation loads than seen in Taiwan.
AA exposure is geographically widespread.
They also found the AA signature in 29% of HCCs from Southeast Asia, in 13% from Korea, and in 2.7% from Japan, as well as in 4.8% and 1.7% of HCCs from North America and Europe, respectively, excluding one US hospital where 22% of 87 HCCs from patients of Asian ethnicity had the signature. “Thus, AA exposure is geographically widespread,” they conclude.
The researchers also observe that in the United States, sale of herbs containing AAs is unregulated, provided such products are correctly labeled and that no health claims are made about them. In addition, “Plants known to contain high concentrations of aristolochic acids are easily available on the internet,” the investigators write.
The study was published online October 18 in Science Translational Medicine.
AA is a natural compound found in Aristolochia and Asarum plant species commonly used in herbal medicine. AA has been linked to multiple cancers as well as kidney failure. Taiwan banned some AA-containing herbal remedies in 2003, and China has restricted use of some AA-containing herbs in traditional medicine. The US Food and Drug Administration has issued warnings regarding consumption of AA-containing products.
Despite the Taiwan ban on AA in 2003, Dr Rozen’s team found no significant difference in the prevalence of the AA signature or in the numbers of AA signature mutations in HCCs diagnosed before and after 2003.
It is possible that the fact that the incidence of AA-associated HCCs has not declined represents a delaying effect following reductions in AA exposure, akin to what has been seen for tobacco-related lung cancer. Ongoing exposure to AA-containing herbal remedies is another possible explanation, they say.
As for the mechanism of AA-induced mutagenesis, “animal studies indicate that AA is absorbed quickly from the alimentary tract into the blood, and eventually the highest concentrations are found in the liver and the kidneys,” Dr Rozen told Medscape Medical News. “After enzymatic bioactivation, AA covalently binds to purines. Some of these are repaired by the cell’s innate DNA repair mechanism, but the ones that are not repaired lead almost exclusively to adenine-to-thymine mutations. We hypothesize that some of these mutations then inactivate genes that prevent cancer or activate genes that promote cancer. These mutations then are ‘hits’ in the usual multi-hit model of cancer development,” he added.
Although there is no treatment specific to AA-associated liver cancers at this point, such cancers often have a high number of mutations, “in which case, speculatively, immunotherapy might more likely be effective,” said Dr Rozen.
Patients with AA-associated liver cancers would likely be at risk for urinary tract cancers, because AA exposure has been independently associated with kidney, upper-track urothelial, and bladder cancers, as well as cholangiocarcinoma. They would also likely be at risk for AA-associated kidney disease and kidney failure, Dr Rozen added.
“Providers could inquire about use of herbal remedies that might contain AA. However, this might be difficult, as there are quite a few AA-containing plants used in herbal medicine, and the species used and the nomenclature depend on the particular herbal medicine tradition,” Dr Rozen said.
“Consumers should avoid herbs that contain AA or that are often confused or substituted for herbs that contain AA. However, I think this is easier said than done without a guide,” he added.
Mislabeling of herbal remedies is common, which suggests that “more thorough methods for testing herbal products, such as chromatographic fingerprinting, combined with regulatory oversight of the supply chain could also help reduce exposure,” the researchers note in their article. “Secondary prevention might take the form of enhanced screening for AA-associated cancers or for kidney disease in patients suspected or known to be exposed to AA,” they conclude.
“Elegant” Work
Reached for comment, Scott L. Friedman, MD, chief, Division of Liver Diseases, the Icahn School of Medicine at Mount Sinai, in New York City, said, “This study illustrates the potential risk of using herbal medicines as treatment for ailments. In this study, a specific component of some herbal medicines, aristolochic acid, induces very specific cancer-causing changes in DNA in liver that leads to liver cancer.
“The work is elegant and carefully performed, and reminiscent of studies decades ago that linked a fungal contaminant, aflatoxin, to a different DNA change that also led to liver cancer,” Dr Friedman said.
The findings underscore the potential risk of any natural or herbal supplement whose contents are not thoroughly characterized.
“The findings underscore the potential risk of any natural or herbal supplement whose contents are not thoroughly characterized in causing unintended and potentially toxic effects, including liver failure and cancer,” Dr Friedman told Medscape Medical News. “This is why we caution our patients to avoid this practice, which is generally more common among Asian patients, especially those who immigrated to the US later in life and continue the practices they learned in their home country.”
The study was supported by the Singapore Medical Research Council, the Singapore Ministry of Health via the Duke-NUS Signature Research Programs, and the Chang Gung Medical Foundation in Taiwan. The authors and Dr Friedman have disclosed no relevant financial relationships.
Sci Transl Med. Published online October 18, 2017. Full text
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