Aristolochic acid
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Aristolochic acids () are a family of
carcinogenic A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
,
mutagenic In genetics, a mutagen is a physical or chemical agent that permanently changes genetic material, usually DNA, in an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer i ...
, and
nephrotoxic Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxins ...
phytochemicals Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poison ...
commonly found in the
flowering plant Flowering plants are plants that bear flowers and fruits, and form the clade Angiospermae (), commonly called angiosperms. The term "angiosperm" is derived from the Greek words ('container, vessel') and ('seed'), and refers to those plants th ...
family
Aristolochiaceae The Aristolochiaceae () are a family, the birthwort family, of flowering plants with seven genera and about 400 known species belonging to the order Piperales. The type genus is ''Aristolochia'' L. Description They are mostly perennial, he ...
(birthworts). Aristolochic acid (AA) I is the most abundant one. The family Aristolochiaceae includes the genera ''
Aristolochia ''Aristolochia'' () is a large plant genus with over 500 species that is the type genus of the family Aristolochiaceae. Its members are commonly known as birthwort, pipevine or Dutchman's pipe and are widespread and occur in the most diverse clima ...
'' and '' Asarum'' (wild ginger), which are commonly used in Chinese herbal medicine. Although these compounds are widely associated with kidney problems, liver and urothelial cancers, the use of AA-containing plants for medicinal purposes has a long history. The
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
has issued warnings regarding consumption of AA-containing supplements.


History


Early medical uses

Birthwort plants, and the aristolochic acids they contain, were quite common in ancient Greek and Roman medical texts, well-established as an herb there by the fifth century BC. Birthworts appeared in Ayurvedic texts by 400 AD, and in Chinese texts later in the fifth century. In these ancient times, it was used to treat kidney and urinary problems, as well as gout, snakebites, and a variety of other ailments. It was also considered to be an effective contraceptive. In many of these cases, birthworts were just some of the many ingredients used to create ointments or salves. In the early first century, in Roman texts, aristolochic acids are first mentioned as a component of frequently ingested medicines to treat things such as asthma, hiccups, spasms, pains, and expulsion of afterbirth.


Discovery of toxicity


Kidney damage

Aristolochic acid poisoning was first diagnosed at a clinic in Brussels, Belgium, when cases of
nephritis Nephritis is inflammation of the kidneys and may involve the glomeruli, tubules, or interstitial tissue surrounding the glomeruli and tubules. It is one of several different types of nephropathy. Types * Glomerulonephritis is inflammation of th ...
leading to rapid kidney failure were seen in a group of women who had all taken the same weight-loss supplement, ''Aristolochia fangchi'', which contained aristolochic acid. This nephritis was termed “Chinese herbs nephropathy” (CHN) due to the origin of the weight-loss supplement. A similar condition previously known as
Balkan endemic nephropathy Balkan endemic nephropathy (BEN) is a form of interstitial nephritis causing kidney failure. It was first identified in the 1920s among several small, discrete communities along the Danube River and its major tributaries, in the modern countries of ...
(BEN), first characterized in the 1950s in southeastern Europe, was later discovered to be also the result of aristolochic acid (AA) consumption. BEN is more slowly progressive than the nephritis that is seen in CHN, but is likely caused by low-level AA exposure, possibly from contamination of wheat flour seeds by a plant of the birthwort family, ''
Aristolochia clematitis ''Aristolochia clematitis'', the (European) birthwort, is a twining herbaceous plant in the family Aristolochiaceae, which is native to Europe. The leaves are heart shaped and the flowers are pale yellow and tubular in form. The plant seeks ligh ...
''. CHN and BEN fall under the umbrella of what is now known as aristolochic acid nephropathy, the prevalent symptom of AA poisoning.


Liver cancer

A study reported in the
Science Translational Medicine ''Science Translational Medicine'' is an interdisciplinary medical journal established in October 2009 by the American Association for the Advancement of Science. It covers basic, translational, and clinical research on human diseases. Accord ...
journal in October 2017 reported high incidences of liver cancer in Asia, particularly Taiwan, which bore the "well-defined mutational signature" of aristolochic acids. The same link was found in Vietnam and other South-east Asian countries. This was compared with much lower rates found in Europe and North America.


Biosynthesis

The herbal drug known as aristolochic acid contains a mixture of numerous structurally related nitrophenanthrene carboxylic acids generally consisting of two major compounds: aristolochic acid I (AA-I) and aristolochic acid II (AA-II). The biosynthesis of these compounds has been of considerable interest due in large part to the inclusion of both an aryl carboxylic acid and an aryl nitro functionality (uncommon in natural products) within their structures, which suggested an apparent biogenetic relationship to the well-known aporphine alkaloids. Furthermore, this association thereby suggested a biosynthetic relationship with norlaudanosoline (
tetrahydropapaveroline Tetrahydropapaveroline (norlaudanosoline) is a benzyltetrahydroisoquinoline alkaloid. It can be formed in trace amounts in the brain by a condensation reaction of dopamine and dopaldehyde (a metabolite of dopamine). It inhibits dopamine uptak ...
) or related benzylisoquinoline precursors, which in turn are derived from
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
(2). Feeding studies (''Aristolochia sipho'') independently using uniquely 14C-labeled compounds -14Ctyrosine, -14Cdopamine and -14Cdihydroxyphenylalanine resulted in the isolation of sup>14CAA-I in each case, which illustrated that the aporphine alkaloid stephanine (11) could be a precursor of AA-I since tyrosine, L-DOPA (3) and dopamine (4) were known precursors of norlaudanosoline: tyrosine (2) is metabolized to L-DOPA (3) which is converted into
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
(4) which is metabolized to 3,4-dihydroxyphenylacetaldehyde (DOPAL); cyclization of these two compounds results in the formation of
norlaudanosoline Tetrahydropapaveroline (norlaudanosoline) is a benzyltetrahydroisoquinoline alkaloid. It can be formed in trace amounts in the brain by a condensation reaction of dopamine and dopaldehyde (a metabolite of dopamine). It inhibits dopamine uptak ...
via a Pictet-Spengler like condensation catalyzed by norlaudanosoline synthetase. Subsequent feeding studies that used (±)‑ 14Cnorlaudanosoline also resulted in the formation of 14C‑labeled-AAI, further suggesting that norlaudanosoline and stephanine (11) could have a possible intermediacy in the biosynthesis of AA-I. Degradation studies of the isolated 14C-labeled AA-I demonstrated that the carbon atom at ring position C4 of the benzyltetrahydroisoquinoline norlaudanosoline was incorporated exclusively in the carboxylic acid moiety of AAI. When this study was repeated but using 14Ctetrahydropapaverine no labeled AAI was isolated; this observation established that a phenol oxidative reaction was required for the biosynthesis of AA-I from norlaudanosoline, further supporting the intermediacy of aporphine intermediates. The results of a feeding experiment (''A. sipho'') with (±)‑ 14C, 15Ntyrosine followed by degradation of the isolated doubly labeled AA-I provided evidence that the nitro group of AA-I originates from the amino group of tyrosine. Confirmation of the involvement of aporphine intermediates in the biogenetic route from norlaudanosoline to AA-I was obtained some two decades later through a series of feeding studies (''Aristolochia bracteata'') using several labeled hypothetical benzyltetrahydroisoquinoline and aporphine precursors. Feeding experiments with (±)‑ ’,8‑3H2; 6-''methoxy''‑14Cnororientaline resulted in the isolation of the doubly labeled AA-I. Cleavage of the methylenedioxy group with trapping of the resulting 14C‑labeled formaldehyde confirmed that this functionality was formed from the ''o''‑methoxyphenol segment of the tetrahydroisoquinoline ring of nororientaline. (±)‑ ’,8‑3H2Orientaline was also incorporated into AA-I. These observations implied that the aporphine prestephanine (10) would be an obligatory intermediate in the biosynthesis, which would involve the intermediacy of the proaporphines orientalinone (8) and orientalinol (9) via the known intramolecular dienone-dienol-phenol sequence for the transformation of benzyltetrahydroisoquinolines to aporphines. A potential role for CYP80G2, a cytochrome P450 that has been demonstrated to catalyze the intramolecular C-C phenol coupling of several benzyltetrahydroisoquinolines, in this orientaline (7) to prestephanine (10) transformation has been suggested. (±)‑ 'aryl''‑3HPrestephanine was incorporated into AA-I confirming its intermediacy in the biosynthesis; and also (±)‑ 'aryl''‑3Hstephanine was incorporated into AA-I. This final transformation, that is stephanine (11) to AA-I (12), involves an uncommon oxidative cleavage of the B ring of the aporphine structure to give a nitro substituted phenanthrene carboxylic acid. Hence, taken together these experiments support the sequence outlined for the biosynthesis of aristolochic acid I from norlaudanosoline.  


Symptoms and diagnosis

Exposure to aristolochic acid is associated with a high incidence of
uroepithelial Transitional epithelium also known as urothelium is a type of stratified epithelium. Transitional epithelium is a type of tissue that changes shape in response to stretching (stretchable epithelium). The transitional epithelium usually appears ...
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
, and is linked to urothelial cancer. Since aristolochic acid is a mutagen, it does damage over time. Patients are often first diagnosed with aristolochic acid
nephropathy Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...
(AAN), which is a rapidly progressive nephropathy and puts them at risk for renal failure and urothelial cancer. However, urothelial cancer is only observed long after consumption. One study estimated, on average, detectable cancer develops ten years from the start of daily aristolochic acid consumption. A patient thought to have AAN can be confirmed through phytochemical analysis of plant products consumed and detection of aristolactam DNA adducts in the renal cells. (Aristolochic acid is metabolised into aristolactam.) Additionally, mutated proteins in renal cancers as a result of
transversion Transversion, in molecular biology, refers to a point mutation in DNA in which a single (two ring) purine ( A or G) is changed for a (one ring) pyrimidine ( T or C), or vice versa. A transversion can be spontaneous, or it can be caused by i ...
of A: T pairings to T:A are characteristically seen in aristolochic acid-induced mutations. In some cases, early detection resulting in cessation of aristolochia-product consumption can lead to reverse of the kidney damage.


Pharmacology


Absorption, distribution, metabolism, and excretion

Once orally ingested, aristolochic acid I is absorbed through the gastrointestinal tract into the blood stream. It is distributed throughout the body via the blood stream. Aristolochic acids are metabolized by oxidation and reduction pathways, or
phase I metabolism Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism (from the Greek xenos "stranger" and biotic "related to living beings") is the set o ...
. Reduction of aristolochic acid I produces aristolactam I which has been observed in the urine. Further processing of aristolactam I by O-demethylation results in aristolactam Ia, the primary metabolite. Additionally, nitroreduction results in an N-acylnitrenium ion, which can form DNA-base adducts, thus giving aristolochic acid I its mutagenic properties. Aristolactam I adducts that are bound to DNA are extremely stable; they have been detected in patient biopsy samples taken 20 years after exposure to plants containing aristolochic acid. Excretion of aristolochic acids and their metabolites is through the urine.


Mechanism of action

The exact mechanism of action of aristolochic acid is not known, especially in regards to nephropathy. The carcinogenic effects of aristolochic acids are thought to be a result of mutation of the
tumor suppressor gene A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...
''
TP53 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often ...
'', which seems to be unique to aristolochic acid-associated carcinogenesis. Nephropathy caused by aristolochic acid consumption is not mechanistically understood, but DNA adducts characteristic of aristolochic acid-induced mutations are found in the kidneys of AAN patients, indicating these might play a role.


Regulation

In April 2001, the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
issued a consumer health alert warning against consuming botanical products, sold as "
traditional medicine Traditional medicine (also known as indigenous medicine or folk medicine) comprises medical aspects of traditional knowledge that developed over generations within the folk beliefs of various societies, including indigenous peoples, before the ...
s" or as ingredients in dietary supplements, containing aristolochic acid.FDA Warns Consumers to Discontinue Use of Botanical Products that Contain Aristolochic acid.
April 11, 2001.
The agency warned that consumption of aristolochic acid-containing products was associated with "permanent kidney damage, sometimes resulting in kidney failure that has required kidney dialysis or kidney transplantation. In addition, some patients have developed certain types of cancers, most often occurring in the urinary tract." In August 2013, two studies identified an aristolochic acid mutational signature in upper urinary tract cancer patients from Taiwan. The carcinogenic effect is the most potent found thus far, exceeding the amount of mutations in smoking-induced lung cancer and UV-exposed melanoma. Exposure to aristolochic acid may also cause certain types of liver cancer.


See also

*
List of herbs with known adverse effects This is a partial list of herbs and herbal treatments with known or suspected adverse effects, either alone or in interaction with other herbs or drugs. Non-inclusion of an herb in this list does not imply that it is free of adverse effects. I ...
* Piperolactam A *'' Stephania tetrandra''


References


Further reading

* * *


External links


Complete list
of warnings from the US
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

FDA Concerned About Botanical Products, Including Dietary Supplements, Containing Aristolochic Acid
May 2000.
Plants Containing Aristolochic Acid

Herbal medicines causing kidney failure, bladder cancer in India
''Times of India'', Mar 19, 2013 {{DEFAULTSORT:Aristolochic Acid IARC Group 1 carcinogens Nitro compounds Phenol ethers Benzoic acids Plant toxins Phenanthrenes Benzodioxoles