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Aristolochic acids are a family of carcinogenic, mutagenic, and nephrotoxic compounds commonly found in the Birthwort (Aristolochiaceae) family of plants. Aristolochic acid (AA) I is the most abundant of the aristolochic acids. The Aristolochiaceae family includes the Aristolochia genus and the Asarum (wild ginger) genus, which are commonly used in Chinese herbal medicine. Although these compounds are widely associated with kidney problems and urothelial cancers, the use of AA-containing plants for medicinal purposes has a long history, and there is controversy regarding their toxicity. Nevertheless, the FDA has issued warnings regarding consumption of AA-containing supplements.

Early medical uses
Aristolochic acid first appeared in Chinese medicine in the 5th century AD, however the Birthwort plants in which it is found are mentioned in ancient Greek and Roman medical texts dating back even earlier. 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, Birthwort plants, and the aristolochic acids they contain, were just some of the many ingredients used to create ointments or salves. In the early 1st 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
Aristolochic acid poisoning was first diagnosed at a clinic in Brussels, Belgium, when cases of nephritis leading to rapid kidney failure were seen in a group of women who had all taken the same weight-loss suplement, Aristolochia fangchi, which contained aristolochic acid. This nephritis was termed “Chinese Herbs Nephropathy” (CHN) due to the origin of the weight-loss supplement. It was later discovered that a similar condition previously known as Balkan endemic nephropathy (BEN), first characterized in the 1950’s in southeastern Europe, was 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. CHN and BEN fall under the umbrella of what is now known as Aristolochic Acid Nephropathy (AAN), the prevalent symptom of AA poisoning.



Biosynthesis
The aristolochic acids are among a group of substituted 10-nitro-1-phenantropic acids, biogenetically derived from benzylisoquinoline precursors, which in turn originate from tyrosine. The biosynthesis of aristolochic acid therefore begins at tyrosine (2), which is converted to dopa (3). Dopa is subsequently converted into dopamine (4) and further converstion of dopamine into 3,4-dihydroxyphenylacetaldehyde (5) results in the formation of norlaudanosoline (6) via a spontaneous Pictet-Spengler condensation of the two molecules. Evidence of these precursors was confirmed by 14C experiments where labeled compounds were administered to Aristolochia sipho and aristolochic acid was successfully extracted. Modification of norlaudanosoline is continued with a methylation of two alcohol groups to give orientaline (7). Orientaline undergoes a cyclization event to give the addition of the 5-membered ring into orientalinol (8), subsequently undergoing a methyl shift and aromatization event (9) to yield prestephanine (10). The final steps are the formation of stephanine (11) and the addition of a carboxylate to yield aristolochic acid (12). Comer et al. originally proposed a postulated pathway from norlaudanosoline to aristolochic acid in 1968 very similar to the described pathway but Sharma et al. confirmed the presence of the intermediate compounds via DL-[3-14C] tyrosine trapping experiments in Aristolochia bracteata in 1982. After the general backbone of aristolochic acid is synthesized, post-synthetic modifications are performed; for example, aromatization of one of the rings yields aristolochic acid I as seen at the top of the page.



Symptoms and diagnosis
Exposure to aristolochic acid is associated with a high incidence of uroepithelial tumorigenesis, 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 (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 estimates that it takes on average ten years from the start of daily aristolochic acid consumption for detectable cancer to develop.

If a patient is thought to have AAN, this can be confirmed through phytochemical analysis of plant products consumed and detection of aristolochic acid DNA adducts in the renal cells. Additionally, mutated proteins in renal cancers as a result of transversion 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.

Absorption
Once orally ingested, aristolochic acid I is absorbed through the gastrointestinal track into the blood stream.

Distribution
It is distributed throughout the body via the blood stream.

Metabolism
Aristolochic acids are metabolized by oxidation and reduction pathways, or phase I metabolism. 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.

Excretion
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. It is thought that the carcinogenic effects of aristolochic acids are a result of mutation of the tumor supressor gene TP53, which seems to be unique to aristolochic acid associated carcinogenesis. Nephropathy caused by aristolochic acid consumption is not mechanistically understood, however DNA adducts characteristic of aristolochic acid induced mutations are found in the kidneys of aristolochic acid nephropathy (AAN) patients, indicating that these might play a role.

Regulation
In April 2001, the Food and Drug Administration issued a consumer health alert warning against consuming botanical products, sold as "traditional medicines" or as ingredients in dietary supplements, containing aristolochic acid. 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.

Controversy
Due to the prevalence of aristolochic acid containing plants in Chinese herbal medicine, there is some controversy regarding the toxicity of these compounds. Much of this debate centers on the cause of the renal failure observed in weight-loss supplement consumers in Belgium. Although, aristolochic acid was originally cited as the cause of nephritis, proponents of Chinese herbal medicine argue that renal failure is generally prevalent in Belgium, and that the patients were on a variety of drugs. Although a variety of animal studies have shown proof of toxicity in the form of nephritis and urothelial cancers, other studies have seen little to no toxicity leaving room for argument.