Aristolochic acid

Early medical uses

Aristolochic acid first appeared in Chinese medicine in the fifth century AD, but 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 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

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 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 (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. CHN and BEN fall under the umbrella of what is now known as aristolochic acid nephropathy, 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 L-DOPA (3). DOPA is subsequently converted into dopamine (4) and further converstion of dopamine into 3,4-dihydroxyphenylacetaldehyde (5) (or 4-hydroxyphenylacetaldehyde to yield reticuline), 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, postsynthetic modifications are performed; for example, aromatization of one of the rings yields aristolochic acid I.

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 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 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.

ADME

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. 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 TP53, 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 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.