Fyziologie působení farmak a
toxických látek
Přednáška č.6
Přírodní toxiny
Toxiny:
= toxické látky nebo jejich směsi produkované
živými organismy;
• mikrobiální toxiny;
• mykotoxiny;
• toxiny produkované řasami a sinicemi;
• toxiny produkované cévnatými rostlinami;
• toxiny živočišného původu.
Bakteriální toxiny – proteiny nebo peptidy, mají
antigenní vlastnosti – cholera toxin, pertussis toxin,
tetanus toxin, botulotoxin, difterotoxin atd. Řada
těchto látek je extémně toxická a postihuje
především nervový, svalový a kardiovaskulární
systém.
Řada bakteriálních toxinů má i praktické využití – př.
Cry toxiny produkované Bacillus thuringiensis,
využívané jako insekticidy.
Enterotoxins
Medical Microbiology, 4th ed., 1996
Cholera is caused by V cholerae, which is usually ingested
in contaminated water. Vibrios that survive passage
through the stomach colonize the surface of the small
intestine, proliferate, and elaborate the enterotoxin.
Cholera toxin acts via adenylate cyclase to stimulate
secretion of water and electrolytes from the epithelial
cells into the lumen of the gut. The duodenum and upper
jejunum are more sensitive to the toxin than the ileum is.
The colon is relatively insensitive to the toxin and may
still absorb water and electrolytes normally. Thus,
cholera is an “overflow diarrhea,” in which the large
volumes of fluid produced in the upper intestine
overwhelm the resorptive capacity of the lower bowel.
Mechanism of action of cholera
enterotoxin. Cholera toxin
approaches target cell surface. B
subunits bind to oligosaccharide
of GM1 ganglioside.
Conformational alteration of
holotoxin occurs, allowing the
presentation of the A subunit to
cell surface. The A subunit enters
the cell. The disulfide bond of
the A subunit is reduced by
intracellular glutathione, freeing
A1 and A2. NAD is hydrolyzed by
A1, yielding ADP-ribose and
nicotinamide. One of the G
proteins of adenylate cyclase is
ADP-ribosylated, inhibiting the
action of GTPase and locking
adenylate cyclase in the “on”
mode
Medical Microbiology, 4th ed., 1996
Crystal (Cry) and Cytolitic (Cyt) protein families are a diverse group of
proteins with activity against insects of different orders—Lepidoptera,
Coleoptera, Diptera and also against other invertebrates such as
nematodes. Their primary action is to lyse midgut epithelial cells by inserting
into the target membrane and forming pores.
Botulotoxin
a neurotoxic protein produced by the bacterium Clostridium botulinum. It is
the most toxic protein known. The toxin is a two-chain polypeptide with a
100-kDa heavy chain joined by a disulfide bond to a 50-kDa light chain. This
light chain is an enzyme (a protease) that attacks one of the fusion proteins
(SNAP-25, syntaxin or synaptobrevin) at a neuromuscular junction,
preventing vesicles from anchoring to the membrane to release
acetylcholine. By inhibiting acetylcholine release, the toxin interferes with
nerve impulses and causes flaccid (sagging) paralysis of muscles in botulism
as opposite to the spastic paralysis seen in tetanus.
Tetanospasmin is the neurotoxin
produced by the vegetative spore of
Clostridium tetani in anaerobic conditions.
The action of the A-chain stops the affected
neurons from releasing the inhibitory
neurotransmitters gamma-aminobutyric acid
and glycine by degrading the protein
synaptobrevin. The consequence of this is
dangerous overactivity in the muscles from
the smallest stimulus-- the failure of
inhibition of motor reflexes by sensory
stimulation. This causes generalized
contractions of the agonist and antagonist
musculature, termed a tetanic spasm.
Toxiny řas a sinic – různé typy nízkomolekulárních
látek odvozených od sinic, rozsivek nebo bičíkovců –
neobvyklé typy aminokyselin
Amnesic Shellfish Poisoning (ASP) was first identified in 1987 from Prince
Edward Island, Canada after four people died from eating contaminated
mussels. It is caused by domoic acid produced by several species of
Pseudonitzschia diatoms. The main contamination problems include mussels,
clams, and crabs of the Pacific Northwest of the United States and Canada.
In mammals, including humans, domoic acid acts as a neurotoxin, causing
short-term memory loss, brain damage and, in severe cases, death. In the
brain, domoic acid especially damages the hippocampus and amygdaloid
nucleus. It damages the neurons by activating AMPA and kainate receptors,
causing an influx of calcium. Although calcium flowing into cells is a normal
event, the uncontrolled increase of calcium causes the cell to degenerate.
Because the hippocampus may be severely damaged, long-term memory loss
occurs.
Microcystins are cyclic nonribosomal peptides
produced by cyanobacteria. They are cyanotoxins
and can be very toxic for plants and animals
including humans. Their hepatotoxicity may cause
serious damage to the liver. Microcystins consist of
several uncommon non-proteinogenic amino acids
such as dehydroalanine derivatives and the special
β-amino acid ADDA ((all-S,all-E)-3-Amino-9-
methoxy-2,6,8-trimethyl-10-phenyldeca-4,6-diene
acid).
Microcystin LR
Rostlinné toxiny – proteiny, peptidy, alkaloidy –
produkty sekundárního metabolismu
The large array of toxic chemicals produced by plants (phytotoxins), usually
referred to as secondary plant compounds, are often held to have evolved as
defense mechanisms against herbivorous animals, particularly insects and
mammals. They include sulfur compounds, lipids, phenols, alkaloids, glycosides,
and many other types of chemicals. Many of the common drugs of abuse such
as cocaine, caffeine, nicotine, morphine, and the cannabinoids are plant toxins.
Many chemicals that have been shown to be toxic are constituents of plants
that form part of the human diet. For example, the carcinogen safrole and
related compounds are found in black pepper. Solanine and chaconine, which
are cholinesterase inhibitors and possible teratogens, are found in potatoes,
and quinines and phenols are widespread in food. Livestock poisoning by plants
is still an important veterinary problem in some areas.
Toxiny hub a plísní – nízkomolekulární látky, peptidy
- produkty specializovaného metabolismu hub
Paličkovice nachová (Claviceps purpurea)
ergotamin
Ergotismus – konvulzívní
a gangrenózní forma,
horčka sv. Antonína
Aflatoxin B1
Aspergillus sp.
Hepatic necrosis, fibrosis
Even at low doses – DNA adducts – mutations;
primary risk factor for hepatocellular carcinoma in
developing countries
Amanita phalloides
phalloidin
Ricin
The seeds of the castor bean (Ricinus communis L.) have been recognised for
their toxicity since times immemorial. As so many poisonous plant materials,
their seeds have been extensively used in folkmedicine against a variety of
illnesses and also for criminal purposes. Castor beans were used in classical
Egyptian and Greek medicine. The main product obtained from the castor
bean is castor oil. It is produced by hot extraction of the beans, a procedure
that destroys the toxin. A minor amount of the oil production is used in
medicine as a laxative, but the major part is used in industry for its
favourable lubricating properties. The ingestion of about five beans appears
to be lethal. This represents a considerable amount of toxin, but being a
protein, ricin is to a large extent destroyed in the intestinal tract.
Therefore, the toxin is about 100 times more toxic when administered
parenterally.
RTA cleaves a glycosidic bond within the large rRNA
of the 60S subunit of eukaryotic ribosomes. RTA
specifically and irreversibly hydrolyses the Nglycosidic
bond of the adenine residue at position
4324 (A4324) within the 28S rRNA, but leaves the
phosphodiester backbone of the RNA intact. The
depurination event rapidly and completely inactivates
the ribosome, resulting in toxicity from inhibited
protein synthesis.
Digoxin
pharmacological effects of digoxin are on the heart. Extracardiac effects are
responsible for many of the adverse effects.
Its main cardiac effects are
* A decrease of conduction of electrical impulses through the AV node, making
it a commonly used antiarrhythmic agent in controlling the heart rate during
atrial fibrillation or atrial flutter.
* An increase of force of contraction via inhibition of the Na+/K+ ATPase pump
(see below).
The chemistry of animal toxins extends from enzymes and neurotoxic
and cardiotoxic peptides and proteins to many small molecules such as biogenic
amines, alkaloids, glycosides, terpenes, and others. In many cases the venoms
are complex mixtures that include both proteins and small molecules and depend
on the interaction of the components for the full expression of their toxic
effect.
The venoms and defensive secretions of insects may also contain many
relatively simple toxicants or irritants such as formic acid, benzoquinone, and
other quinines, or terpenes such as citronellal.
Snake venoms have been studied extensively; their effects are
due, in general, to toxins that are peptides with 60 to 70 amino acids.
These toxins are cardiotoxic or neurotoxic, and their effects are usually
accentuated by the phospholipases, peptidases, proteases, and other
enzymes present in venoms. These enzymes may affect the blood clotting
mechanisms and damage blood vessels.
Many fish species, over 700 species worldwide, are either directly
toxic or upon ingestion are poisonous to humans. A classic example is the
toxin produced by the puffer fishes (Sphaeroides spp.) called
tetrodotoxin (TTX). Tetrodotoxin is concentrated in the gonads, liver,
intestine, and skin, and poisonings occurs most frequently in Japan and
other Asian countries where the flesh, considered a delicacy, is eaten as
“fugu.” Death occurs within 5 to 30 minutes and the fatality rate is about
60%. TTX is an inhibitor of the voltage-sensitive Na channel; it may also
be found in some salamanders and may be bacterial in origin.
http://www.toxinology.com/