ARISTOLOCHIC ACID, ARISTOLACTAM I and DNA Adducts
It is a poisonous plant once cultivated in ancient Greece and in Roman times for its medicinal purposes (its ability to treat kidney and urinary problems) and for weight-loss and for its supposed help in child birth as an aid to abortion (it is an abortifacient) - which was based solely on the resemblance of the flower shape to that of the birth canal in the infamous 'Doctrine of Signatures'. It has now been superseded by much safer alternatives. The scientific name of the plant, Aristolochia derived from the Greek aristos meaning 'best' and locheia 'childbed' meaning 'childbirth'. The use of this plant could lead to nephritis (inflammation of the kidneys) and rapidly result in kidney failure. Urothial cancers can also result from the medicinal use of this plant after about 10 years.
It was much later found that the active ingredient responsible for both the beneficial effects and the deleterious effects was
Aristolochic Acid I, AA I, which is, like the flowers of Birthwort, yellow in colour. Chemically it is a modified
phenanthracene with dioxole, methoxy, carboxilic acid and nitro groups attached in various places. Although it contains nitrogen, it is not technically an alkaloid for the nitrogen is not incorporated within a ring, but appears as a -nitro side-group. When ingested, the metabolites of Aristolochic Acid (
Aristolactam I) can enter the cell nucleus and form DNA Adducts by the alkylation process, thus putting a spanner in the workings causing DNA replication errors. The adducts have a preference for Adenosine bases which causes A to T transversions, substituting Tyramine for Adenosine. The metabolites seem to show a preference for CAG and TAG sequences in the DNA. Aristolactam I adducts are extremely stable and have been detected in patients 20 years after exposure to Aritolochic Acid. Aristolochic Acid is thus classed as a Group 1 carcinogen. Because of its carcinogenic properties Aristolochic Acid is no longer allowed in pharmaceutical products.
Besides Aristolochic Acid I, there are said to be three other very similar Aristolochic Acids within Birthwort, called Aristolochic Acid II, Aristolochic Acid III, Aristolochic Acid IV, although your Author can only find structural formulae for the first two.
Reticuline, an isoquinoline alkaloid, is one of the intermediary products which Birthwort produces in synthesizing Aristolochic Acid. Birthwort also contains the toxic Aporphine alkaloid
Magnoflorine which is found in some members of the Poppy Family (Papaveraceae). Magnoflorine bears many similarities to Aristolochic Acid, apart from the heterocyclic nitrogen atom which is incorporated into the ring.
The caterpillar larvae of
Swallowtail butterflies protect themselves from being eaten by mealing on species of Aristolochia, of which there are over 500 in the World. Many other Lepidoptera species (which includes moths and butterflies) also consume Aristolochia plants, probably for similar reasons.
MODUS OPERANDI - DNA adducts with ARISTOLOCHIC ACID I
Aristolochic Acid I (or equally Aristolochic Acid II) - can both engage in forming adducts with DNA, as shown above. Aristolochic Acid I is acted upon by two enzymes contained within the mammalian body which put the exocyclic Nitrogen atom into a new ring, thus now making it a true alkaloid, called N-HydroxyAristoLactam I. This quickly changes form to the nitrenium ion version of AristoLactam I by losing one of its oxygen atoms but gaining several other hydrogen atoms (2?), leaving the molecule with a concentration of positive charge near the nitrogen atom which now has the wrong valency, 2 instead of the normal 3. This nitrenium ion molecule is attracted to DNA molecules forming a DNA adduct. It can form DNA adducts with either the Adenosine bases or the Guanine bases within the DNA, but is especially attracted to those parts in the DNA where there is either a CAG sequence or a TAG sequence of bases. [There are only 4 bases within DNA, A - Adenine, G - Guanine, T - Thymine and C - Cytosine]. The DNA part consists of a base attached to a d-Ribose sugar unit, which are just one component of the extremely long double helix that is DNA. By so attaching to a base, this prevents proper reading or duplication of the DNA, leading to errors in replication called mutations.
These DNA adducts are persistent within the human body and can still be detected 20 years after any treatment with Aristolochic Acid or Birthwort extracts containing the active ingredients, Aristolochic Acids.
All is not lost, however, there are enzymes within the body which will change the intermediate N-HydroxylAristoLactam I into safe products before it is converted into the very potent nitrenium ion of AristoLactam I. But seemingly(?), they cannot detoxify any DNA adducts which have already formed.
Aristolochic Acid can attack any part of the genome with equal probability. It is known to cause liver cancer.