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Plants
from the genus Aristolochia have been
used medicinally for more than 2,500 years.1 The toxicity associated
with aristolochic acid (AA) — a chemical produced by the plants — has become
well established in only the last 2 decades. Today, AA is known to be a potent
human carcinogen and beginning in 2000, the US Food and Drug Administration
(FDA) issued an import alert and consumer advisory and sent letters to industry
and health professionals, effectively banning the substance from the
marketplace.2
Additionally,
in 2001, the American Herbal Products Association (AHPA) adopted a trade
requirement banning the sale of any herbal products containing AA. On its
website, AHPA cites 2 FDA documents that list botanicals known or suspected to
contain AA. The documents also include plants that are occasionally adulterated
with Aristolochia species, such as
certain plants from the genera Akebia, Clematis,
Cocculus, Diploclisia, Menispernum,
Saussurea, Simomenium, Stephania,
and Vladimiria.3 The list
also includes the genus Asarum, which
is not an adulterant per se, but an AA-containing plant and a member of the
family Aristolochiaceae.
Earlier
this year, using advanced genetic analyses, scientists found that exposure to
AA from Chinese herbal medicines contributed significantly to the rate of upper
urinary tract cancer (UUC) in Taiwan, where the incidence is the highest in the
world. The findings were published online in the April issue of Proceedings of the National Academy of
Sciences (PNAS).4
“Aristolochic
acid is a powerful, irreversible nephrotoxin [(kidney toxin)],” said Arthur P.
Grollman, MD, a professor in the Departments of Medicine and Pharmacological
Sciences at Stony Brook University in New York and a co-author of the recent PNAS
paper (e-mail, May 24, 2012). “Clearly, any use of Aristolochia herbs for medicinal purposes should be avoided.”
The
damaging effects of AA received international media attention in the early
1990s when dozens of Belgian women developed kidney failure after inadvertently
ingesting A. fangchi
(Aristolochiaceae) as part of a weight-loss regimen.4 “The use that
resulted in kidney failures and deaths were due to adulteration [of] the herb Stephania tetrandra [(Menispermaceae)],
[for which] A. fangchi was considered
an acceptable substitute for many years,” said Roy Upton, president of the
American Herbal Pharmacopoeia (AHP) (e-mail, May 22, 2012).
“It
apparently arose as an adulterant in the 1950s due to the nomenclatural
similarity between Stephania (fang ji or han fang ji) and A. fangchi
(guang fang ji),” he continued. “In
my opinion, the adulteration was completely accidental due to nomenclatural
confusion.”
In 2006,
AHP produced the 214-page technical paper “Characterization of Selected Plants
That May Contain or be Adulterated With Aristolochic Acid.” The monograph,
which is available for purchase on AHP’s website, provides detailed information
on the macroscopic, microscopic, and phytochemical characterization of
AA-containing plants, as well as
those plants that do not contain AA but may inadvertently be tainted with
adulterants. The paper also includes information on high-performance liquid
chromatography (HPLC) — the FDA-preferred method of botanical analysis — as a
means of detecting AA in plants.5
In an article dealing with the AA adulteration
issue that appeared in HerbalGram
#48, author and Chinese medicine expert John Chen, PhD, Pharm. D, LAc, of Lotus Herbs
and Lotus Institute emphasized the importance of proper
identification techniques to ensure the safety of botanical products.6
“Physical inspection is the most commonly used method of identification.
However, it is not 100 percent accurate or reliable,” he wrote. “Laboratory
techniques such as high performance liquid chromatography, thin-layer
chromatography, and liquid-column chromatography must be used to confirm
qualitative and quantitative analyses of the various herbs’ chemical profiles.”
Aristolochic
acid has also been implicated as the cause of widespread kidney problems first
reported more than 50 years ago in rural areas of Bulgaria, Croatia, Bosnia and
Herzegovina, Romania, and Serbia. In 2006, researchers discovered the source of
the problem to be exposure to AA through the consumption of bread made with
seeds of A. clematitis.4, 7
Using
detailed medical records from Taiwan’s National Health Insurance database — which
covers roughly 96% of the country’s residents — researchers previously have
estimated that one-third of the population has used herbal products that
contain or are likely to contain AA.8 “The remarkably high incidence
of UUC, coupled with the widespread use of Aristolochia
herbal remedies, suggested that AA might play a central role in the etiology of
[upper urinary tract carcinomas],” wrote the authors of the recent PNAS paper.
Aristolochic
acid causes immediate damage to human genetic material. As AA is broken down in
the body, it reacts with DNA to form lesions that concentrate in the kidneys.
Additionally, exposure to AA results in unique, detectable mutations in certain
tumor-suppressing genes. Combined, these changes provide a highly traceable
signature of AA exposure.4
In the
PNAS study, Dr. Grollman and his colleagues examined 151 patients with UUC for
the specific biomarkers associated with AA exposure. Eighty-four percent of
participants with tumor-suppressing gene mutations were also found to have
lesions present in their renal cortex, strongly suggesting exposure to AA.
The
researchers concluded that “persons treated with Aristolochia herbal preparations at any time in their life are at
significant risk of developing UUC or chronic renal disease.”
Determining
one’s level of exposure to AA, however, can be challenging. “Most people would
not know if they took an AA-containing plant unless they still had part of
their formula and tested the ingredients,” explained Upton.
“The
herbs that historically have been most associated with AA adulteration include Akebia (mu tong), Clematis (wei ling xian), and Stephania (fang ji). The
most popular formulas subject to AA adulteration historically were Long Dan Xie Gan Tang (Gentiana Decoction to Drain the Liver) and Ba Zheng San (Eight-Herb
Powder for Rectification). Both formulas contain Akebia (mu tong), an herb
that can be mistakenly compounded with the AA-containing Aristolochia manshuriensis (guan mu tong),” Upton added. “In North
America, these would likely be the most common formulas to have been
adulterated. There is not a general concern regarding use of Chinese herbal
medicines as adulteration typically occurs in very specific instances with very
specific ingredients.”
According
to Dr. Chen, the use of herbs that contain AA, such as guang
fang ji (A. fangchi) or guan mu tong
(A. manshuriensis), are banned not only in the
United States and the European Union, but also in Taiwan and many countries in
Asia. “In fact,” he wrote in an email, “in a drastic measure to avoid any
future incident, merchants in Taiwan who sell [these herbs] are subject to
criminal charges.” (J. Chen email, June 4, 2012).
Despite
existing regulations, Dr. Grollman and his colleagues concluded that exposure
to aristolochic acid has “significant implications for global public health.”
According to Upton, “The issue of AA toxicity has been actively addressed by
regulators and responsible elements of the herb industry worldwide who have
taken steps to keep AA-containing herbs out of the market. Hopefully this will
be considered a problem that once existed rather than an ongoing concern.”
—Tyler Smith
References
1. AP Grollman, J Scarborough, and B
Jelakovic. Aristolochic acid nephropathy: An environmental and iatrogenic
disease. Advances in Molecular Toxicology.
2009. 3:211-227.
2. Aristolochic Acid: FDA Concerned About Botanical Products, Including
Dietary Supplements, Containing Aristolochic Acid. US Food and Drug
Administration website. Available at: www.fda.gov/Food/DietarySupplements/Alerts/ucm095302.htm. Accessed May 29, 2012.
3. Code of Ethics and Business Conduct. AHPA website. Available at:
www.ahpa.org/Portals/0/pdfs/AHPA_CodeOfEthics.pdf. Accessed May 31, 2012.
4. Chung-Hsin C, Dickman
KG, Moriya M, Zavadil J, Sidorenko VS, Edwards KL, et al. Aristolochic acid-associated urothelial cancer in Taiwan.
PNAS. Available at: www.pnas.org/content/early/2012/04/03/1119920109.abstract. Accessed May 30, 2012.
5. Aristolochic Acid Evaluation Monograph. American Herbal Pharmacopoeia
website. Available at: www.herbal-ahp.org/arist_program.htm. Accessed May 31,
2012.
6. Chen J. Nephropathy
associated with the use of Aristolochia. HerbalGram. 2000; 48:44-45. Available at: http://cms.herbalgram.org/herbalgram/issue48/article374.html.
Accessed May 31, 2012.
7. Re: Urinary Cancer Associated with Chinese Herb
Aristolochia. Herb Clip. Available at:
http://cms.herbalgram.org/herbclip/185/review42980.html. Accessed June 3, 2012.
8. Ming-Nan L, Shuo-Meng W,
Pau-Chung C, Ya-Yin C, Jung-Der W. Population-Based case–control Study of
Chinese herbal products containing aristolochic acid and urinary tract cancer
risk. Journal of the National Cancer Institute. 2009.
102(3):179-186. Available at:
http://ntur.lib.ntu.edu.tw/bitstream/246246/233164/1/No.312.pdf. Accessed May
30, 2012.
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