First acquaintance of a text: the ill-fated aristolochic acid!

In 2013, scholars in Singapore and Taiwan found that aristolochic acid can cause urinary tract epithelial cancer, with 150 mutation points per million genes
.

In 2017, the "Translational Medicine" sub-issue of the internationally renowned journal "Science" published a cover article titled "Aristolochic acid and its derivatives are widely associated with liver cancer in Taiwan and throughout Asia"
.
According to the article, researchers have sequenced and analyzed more than 1,400 liver cancer samples worldwide and found that the aristolochic acid exposure imprints of Chinese samples were significantly higher than those of North American and European samples, and concluded that the occurrence of liver cancer in Asia is related to Aristolochia The conclusion that there is a correlation between acid exposure
.

02

What kind of Chinese herbal medicine does aristolochic acid come from?

Aristolochic acid, first isolated from clematis-shaped aristolochia, is an alkaloid, also known as total aristolochic acid, phagocytic acid or xylotonin, which is a kind of strong carcinogenic Sexual and nephrotoxic nitrophenanthrene carboxylic acid
.
According to relevant information, the plants containing aristolochic acid in nature are mainly Aristolochia plants, with a total of more than 600 species in 8 genera, and about 70 species in 4 genera in China
.
Many medicinal plants well-known to the Chinese, such as Guanmutong, Guangfangji, Qingmuxiang, Aristolochia, Xungufeng, Asarum, Nanmuxiang, Guannanxiang, etc.
, all contain aristolochic acid
.
Commonly used Chinese patent medicines include Longdan Xiegan Pills, Fuke Fenqing Pills, Dahuang Qingwei Pills, Guanxin Suhe Pills and so on
.

   
03

Talking about Aristolochic Acid from the Perspective of Traditional Chinese Medicine

Traditional Chinese medicine theory believes that Chinese herbal medicines of the genus Aristolochia have diuretic, anti-infective, anti-inflammatory and anti-snake venom functions
.
Chinese herbal medicines and Chinese patent medicines containing aristolochic acid have been used to treat various diseases such as rheumatism, gout, wound suppuration, and are widely used to alleviate women's menstrual symptoms and relieve pain during childbirth
.
In addition, it has also been widely used in Asia, being added to medicinal wine, ointments and weight loss drugs
.

  
04

Talking about aristolochic acid from the perspective of medicinalization

Aristolochic acid (AA) is the first nitro compound found in the plant kingdom.
It is a derivative of 3,4-Methylenedioxy-10-nitro-1-phenanthrene acid, which is similar in structure It is composed of a variety of nitrophenanthrene carboxylic acids, which mainly contain aristolochic acid I (AAI) and aristolochic acid II (AAII) (the position of the methoxy group can be divided into aristolochic acid I, II, III, Ⅳ)
.

AAI is the main toxic component of aristolochic acid, which generates 8-hydroxy-aristolochic acid I (AAIa) after oxidative metabolism in the body, thereby reducing the nephrotoxicity caused by AAI
.
AAI undergoes reduction metabolism to form unstable circularized positive nitrogen ions, which can covalently bind with DNA to form AAI-DNA adducts
.
The AAI-DNA adduct has been confirmed in the urethral epithelial tissues of experimental animals given AAI and AAN patients
.

05

Talking about Aristolochic Acid from the Perspective of Toxicology

Toxic dose

Studies have analyzed the risk of AA leading to end-stage renal disease and UUC.
The calculated lower limit of the threshold dose confidence limit (BMDL) for ESRD caused by AA is 0.
42 g (cumulative amount), and the combined OR of cancer caused by AA is 5.
97 (95% confidence interval CI, 2.
78-12.
84), using AA-containing drugs or eating food mixed with seeds of Aristolochiaceae plants can increase the risk of ESRD and UUC
.

Nephrotoxicity

AAI is transported by organic anion transporter 1 (OAT1)
.
After entering the renal tubular cells, the cytotoxic effect of AAI on the renal tubules can interfere with the substrate transport function of OAT1
.
After the rat organic anion transporter (OAT1) transfected human embryonic kidney 293 cells (HEK293) were incubated in the AAI-containing incubation solution, the AAI concentration in the cells was positively correlated with the AAI concentration of the incubation solution and the incubation time, and apoptosis was also followed.
Increase
.
The administration of AAI in rats can significantly reduce the expression of OAT1 in the basement membrane, and reduce renal excretion rate and renal tubular damage
.

Mutagenic

Guanmutong contains AAI and AAⅡ, and the contents of AAI and AAⅡ are about (2.
85±0.
08) and (0.
50±0.
02) mg·kg-1, respectively
.
Guanmutong can increase the number of bacterial back mutations in a dose-dependent manner, and lead to an increase in the incidence of chromosomal aberrations in Chinese hamster ovary K1 cells; Guanmutong 5g·kg-1 group micronucleus test was positive
.
The mutagenic effect of Guanmutong is related to its AA content
.
Aristolochia and Asarum contain AA.
Studies have shown that tinctures containing the above-mentioned plants can inhibit the DNA synthesis of human liver cancer Hep G2 cells in a dose-dependent manner and arrest cell proliferation in the S phase
.
After metabolic activation, AA can react with d A and d G residues to form aristolochic acid lactam DNA adducts, which can quickly enter the renal tubular epithelial cells and accumulate in the cells, resulting in TP53 from A:T to T:A Studies have shown that this kind of mutation is mainly located in the non-transcribed chain and is difficult to be recognized by the whole-genome nucleotide excision repair.
This may be the reason for the high mutagenic activity and long duration of AA
.

Detoxification mechanism and therapeutic drugs

Human liver microsomal cytochrome P450CYP1A1/2 plays an important role in the oxidative and metabolic clearance process from AAI to AAIa.
Inhibition or loss of its activity will lead to increased nephrotoxicity of AAI
.
Tanshinone I can induce liver CYP1A1/2 activity in mice, promote the metabolism of AAⅠ, and reduce the liver damage caused by it
.
The oxygen concentration in body tissues can affect the balance of AAI nitro reduction or demethylation metabolism, and then affect the toxicity and carcinogenicity of AAI to local tissues
.

06

Viewing the IP of Aristolochic Acid from the Perspective of Patent

Although people’s awareness of the toxicity and hazards of aristolochic acid has become increasingly clear, the number of patent applications for inventions containing aristolochic acid has not been affected by this.
Since 2004, the number of applications each year has been increasing compared with 2003.
It reached the peak of 20 items in 2013.
Although there was a decline in 2014 and 2015, the overall situation is still growing
.

Among the 88 invention patent applications involving aristolochic acid filed with the State Intellectual Property Office of China, 46 related to the detection method of aristolochic acid; 14 related to medical devices using aristolochic acid; in addition, It relates to a method for the enrichment of aristolochic acid in traditional Chinese medicines, a method for processing aristolochic acid-containing medicines, and a processing method for aristolochic acid-containing traditional Chinese medicines
.
Among the applicants for aristolochic acid invention patents, there were only 14 individual applications, and the remaining applicants were scientific research institutions and enterprises
.
It can be seen that in addition to scientific research institutions, pharmaceutical companies are also very enthusiastic about the research and development of products and methods involving aristolochic acid
.

The author's feelings

First of all, I want to understand the whole story of the aristolochic acid incident because I have recently read some literature related to gene toxicity, which has generated interest; secondly, there are not many Chinese medicine products whose main ingredients have been questioned and studied to this degree.
; Again, don't slap Chinese medicine to death because of aristolochic acid!

Although the author is engaged in the development of new western medicines, I also approached the direction of Chinese medicine with a research attitude.
Once upon a time, I was also affected by some "hate" Chinese medicines.
However, as my experience of Chinese medicine deepens and deepens.
There is still much to be done to feel the direction of Chinese medicine in our country, but how to integrate standards and methods with Western medicine, or how to establish a more scientific and complete evaluation system of its own, requires a lot of effort
.
As mentioned in this manuscript, the depth of research on aristolochic acid stems from its toxicity, rather than the depth of research guidelines.
This is contrary to the nature and logical sequence of western medicine research and development.
Many Chinese medicines are questioned.
That's why everywhere
.
Therefore, the development of traditional Chinese medicine in my country is a long way to go.
Although it is difficult, it has to be subdivided and deepened.
There are too many "whys" to give reasonable data!