Transcript aristolochic_acidx

Terisse Brocato
Miguel Pena
Stephen Esquivel
Victor Salgado
A
toxin is a substance (poisonous) produced
by an organism that may have an adverse
affect on another organism.
 Toxins
can be produced as a defense
mechanism for an organism as well as an
offensive mechanism.
 Aristolochic
Acid is a family of compounds
that are commonly found in the
Aristolochiaceae family of plants that
produce carcinogenic, mutagenic, and
nephrotoxic effects.
 Aristolochic
Acid is a commonly used
ingredient in various Chinese herbal
medicines as well as other herbal remedies.
 Aristolochic
acid was first determined to be
toxic when the makers of a slimming drug in
Belgium was replaced with AA.
 Hundreds
of cases of Aristolochic acid
nephropathy (AAN) came about due to the
intake of AA which was used in many herbal
remedies all over the world.
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Obstetrics treatment
Snakebites
Scorpion stings
Fever
Infection
Diarrhea
Inflammation
 Arthritis
 Gout
 Rheumatism
 Festering
wounds
 Weight-loss
 Eczema
 Hepatitis B
 Pain relief
 Aristolochia
debilis
 Aristolochia manshuriensis
 Aristolochia fangchi
 Aristolochia contorta
 Little Brown Jug
 Canadian snakeroot/ Wild ginger
 Virginia snakeroot
 Asarum canadense
 Tian-Xian-Teng
 Ma-Dou-Ling
 Qingmuxiang
 Guangfangji
 Guanmutong
 han
fang
 ba zheng san
 Dao Chi Pian
 Chuan Xiong Cha Tiao San
 Lung Tan Xie Gan
Belgium: 128
Germany: 1
UK:4
USA:2
Korea:1
France:4
Japan:6
Spain:1
Taiwan:33
China:116
The major outbreaks were in Belgium and China where containing AA
was common (weight loss drug, and treatment of urinary and
cardiovascular disease)(Debelle et al).
The two major components of Aristolochic Acid are Aristolochic
acid I (AAI) and Aristolochic acid II (AAII)
1.
Kidney Problems (AA is a nephrotoxin)
2.
Cancer (due to metabolism of AA)
3.
Heart problems
 Shrunken
kidneys (majority of cases)
 Asymmetric
 Interstitial
kidneys (half of cases)
fibrosis (thickening of kidney wall
fibers)
 Atrophy
of kidneys (degeneration and death
of kidney cells)
This is a picture of a normal functioning kidney and its functions in the
body.
A patient subjected to AA will have the following problems with
their kidneys.
 39.5%
of patients with a kidney transplant
are diagnosed with bladder urothelial
carcinoma.
 Cancer
is caused by DNA adducts which form
by AA metabolism.
 Animal
tests show that DNA adducts remain
in animal’s bodies throughout their life (this
has not yet been tested in humans).
 30-50%
of patients diagnosed with AAN
(Aristolochic acid nephropathy-kidney
damage due to taking AA) have aortic
insufficiency (where the aortic valve is not
able to close completely, causing backflow of
blood from the aorta to the left ventricle).
 This
causes the heart to pump harder in
order to pump enough blood to the body.
The products of metabolism, dA-AAI/II and dG-AAI/II, are
DNA adducts which form mutations in DNA
 Metabolism
of AA in the body forms DNA
adducts (dA-AAI/II, dG-AAI/II) which are
known to cause particular mutations
(mutations depend on species).
 In humans: there is an ATT->TAG mutation in
the p53 gene.
 In rodents: there is an AT->TA mutation in the
H-ras proto-oncogene.
 Both mutations cause tumorigenesis
(formation of tumors).
Metabolism of Aristolochic acid is
known to cause fibrosis of the
kidneys. Scientist suspect
causation can happen via small
doses over a long time or by large
doses at intermediate intervals.
A) shows a complete loss of
microvilli of the inner kidneys. B)
shows disruption of the cellular
adhesion molecules between
cells.
 Transforming
Growth Factor 1 beta and its
conjugate SMAd complex may play a role in
Aristolochic acid signaling and metabolism.In
A 2009 study scientists chronically exposed
mice with the wild-type smad3 mediator and
mice with knock-out smad3 mediator with
aristolochic acid. The wild-type mice were
found to have nephropathy, characterized by
fibrosis and scarring. The knockout mice did
not exhibit Nephropathy.
TGF 1 BETA is a known factor in tissue scaring by inducing
fibrosis via the downstream SMAD3 mediator. Aristolochinc
acid was found to cause no fibrosis in mice that did not
have have functional SMAD3 receptors. This a mechanistic
look at how Aristolochic acid causes nephropathy.
Compromisation of the TGF-1 Beta signal causes
dissolution of the connective properties of epithelial cells
which acquire a mesenchymal phenotype. Actin
reorganization and stress fiber formation support
migration and invasion of epithelial cells to other sites.
Aristolochic acid is found to induce fibrosis(scaring) via
the TGF1 Beta/SMAD3 pathway.
 Balkin-endemic
nephropathy (BEN)
 Patients suffering from BEN are found to
have all the same cancers, renal problems,
and overall same symptoms, but with minor
variations as patients with Aristolochic acid
nephropathy (AAN).
 It is highly suspected that BEN is caused by
long-term exposure to small amounts of AA.
 This conclusion is popular due to the fact
that many third-world countries use herbal
remedies containing AA for various reasons:
to treat diseases, sickness, pain, etc.
 At
least 25000 individuals are suffering with
BEN in Bulgaria, Bosnia, Croatia, Romania,
and Serbia.
 Total
people at risk in these countries may be
higher than 100,000 (Debelle et al.)
 Most
citizens in these places do not have
adequate access to information on the
medicines which they take, nor is the
medicine labeled adequately.
 Short
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Removal of toxin from the body
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Term-
Dialysis (if needed)
Kidney Transplant (severe cases)
Supportive Therapy in acute phase
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Fluid and electrolyte management
Management of hypertension
Dialysis for acute severe renal failure
 High
risk of substitution in herbal products
causes misperception of what an individual is
taking.
 Testing of herbal remedies using high-liquid
chromatography or some characterization
method should be used before allowing any
herbal remedy to be ingested.
 AA should not be ingested for any reason,
unfortunately Chinese medicine and Indian
folk medicine still use AA in their herbal
remedies.
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Debelle et al. “Aristolochic acid nephropathy: A worldwide problem”.
2008 International Society of Nephrology. Kidney International
(2008) 74, 158–169.

Jain Xu, et al. “TGF--induced epithelial to mesenchymal transition” Cell
Reserch. Vol 19. 157-172. (2009)

Li Zhou, et al. “Mechanism of chronic
aristolochic acid
nephropathy:
role of Smad3” American Journal of Renal
Physiology. Vol 298.
no. 4. 1006-1017 (2010)

Lord et al. “DNA Adducts and p53 Mutations in a Patient With Aristolochic
Acid–Associated Nephropathy”. American Journal of Kidney
Diseases, Vol 43,
No 4 (April), 2004: E18.

Mary Packard, et al. “Wnts and TGF in synaptogenesis: old friends
signalling at new places” Nature Reviews Neuroscience. Vol 4.
113-120 (February 2003)

Mengs et al. “The Carcinogenic Action of Aristolochic Acid in Rats”.
Archives of Toxicology (1982) 51:107-119.
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National Toxicology Program,U.S. Department of Health and Human
Services. “Report on Carcinogens- Background Document for
Aristolochic Acids”. September 2008.
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Schmeiser et al. “Detection of DNA Adducts Formed by Aristolochic Acid
in Renal Tissue from Patients with Chinese Herbs Nephropathy”.
Cancer Research Vol 56, 2025-2028, May I. I996.
Shaohua et al. “Fatal renal failure due to the Chinese herb ‘‘GuanMu
Tong’’ (Aristolochia manshuriensis): Autopsy findings and review of
literature”. Forensic Science International 199 (2010) e5–e7.
Stiborov et al. “Bioactivation versus Detoxication of the Urothelial
Carcinogen Aristolochic Acid I by Human Cytochrome P450 1A1 and
1A2”. ToxicologicalSciences 125(2), 345–358
(2012).
Yee-Yung Ng, et al. “Tubular epithelial-myofibroblast transdifferentiation
in progressive tubulointerstitial fibrosis
in 5/6
nephrectomized rats” Kidney
International. Vol 54.
864876. (1998)
Youhua Liu. “Renal fibrosis: New insights into the pathogenesis and
therapeutics” Kidney International. Vol 69. 213-217. (2006)
Zeng et al. “Aristolochic Acid I Induced Autophagy Extenuates Cell
Apoptosis via ERK 1/2 Pathway in Renal Tubular Epithelial Cells”.
Department of Nephrology. January 2012, Volume 7, Issue 1,
e30312.