... enters the food chain when the mussels fed on Dinophysis
acuminata Routes of intoxication : consumption of
shellfish
Symptoms & signs (diarrhetic
shellfish poisoning (DSP)) : diarrhea
=> saxitoxins / PSP toxins (PSTs) enters
the food chain when the mussels fed on Gonyaulacaceae.
Softshell clams (Mya
arenaria) from areas exposed to 'red tides' are more resistant
to PSTs, as demonstrated by whole-nerve assays, and accumulate toxins at
greater rates than sensitive clams from unexposed areas. PSTs lead to selective
mortality of sensitive clams. Resistance is caused by natural mutation
of a single amino acid residue, which causes a 1,000-fold decrease in affinity
at the saxitoxin-binding site in the sodium channel pore of resistant,
but not sensitive, clams. Thus PSTs might act as potent natural selection
agents, leading to greater toxin resistance in clam populations and increased
risk of PSP in humans. Furthermore, global expansion of PSP to previously
unaffected coastal areas might result in long-term changes to communities
and ecosystemsref.
Routes of intoxication : human LD50
for ...
ingestion : 5.7 µg/kg, therefore approximately 0.5 mg of saxitoxin
is lethal if ingested. This toxin is not heat-sensitive; even proper cooking
will not lessen its effect
injection : 0.6 µg/kg
inhalation : 5 mg/min/m3.
open wounds : 0.05 mg/person
Saxitoxin is 1,000 times more toxic than the potent nerve gas sarin.
Symptoms & signs (paralytic
shellfish poisons (PSPs)) : occur between 10' and 4 hours after ingestion,
depending on the dose. Inhalation of the toxin will produce a more rapid
onset of symptoms, and, injection of saxitoxin may cause death in <
15'. The clinical signs of PSP include paresthesias of the lips, tongue,
and gums, rapidly progressing to involve the distal extremities. Headaches,
ataxia, muscle weakness, paralysis, and cranial nerve dysfunction have
also been reported; the moderate to severe hypotension in puffer fish is
not usually seen in PSP (Kao CY. Paralytic shellfish poisoning. In: Algal
Toxins in Seafood and Drinking Water. Falconer IR (ed). NY: Academic Press,
1993: pp 75-86). Gastrointestinal signs such as nausea, vomiting, abdominal
pain and diarrhea are less common. Generally, fatalities occur within the
1st 12 hours of clinical signs, and death is usually from respiratory failure.
PSP usually lasts 3 days, but muscle weakness may persist for weeks. Cardiac
arrest is not generally associated with PSP. If a victim survives
for 12 hours, he has a good chance of recovering as the toxin is rapidly
removed from the body. There is no specific antidote therapy, only symptomatic
treatment; mechanical ventilation has been used successfully in some cases.
Identification of saxitoxin as a cause of intoxication by virtue of clinical
symptoms is not simple but is very importrant for military medicine, because
faulty identification of this toxin as nerve gas poisoning may be fatal
and administration of atropine would increase
fatalities. PSP has been known to have a death rate of 1-12%
=> domoic acid / amnesic
shellfish toxin
enters the food chain when the mussels fed on a toxic algal bloom of the
pennate diatom Pseudo-nitzschia
pungens
forma multiseries and Pseudo-nitzschia
delicatissima Epidemiology : in 1987, 150 reported cases,
19 hospitalisations and 4 deaths following the consumption of blue mussels
caught off Prince Edward Island, Canada
Routes of intoxication : consumption of
shellfish
Symptoms & signs (amnesic
shellfish poisoning (ASP)) : gastrointestinal disturbances and neurotoxic
effects such as hallucinations, memory loss and coma
=> brevetoxins enters the food chain
when the mussels fed on Karenia brevis Epidemiology : a long history of toxic
microalgal blooms exists in the Gulf of Mexico, blooms that have caused
massive fish kills and respiratory irritation in humans. It was later realized
that BVX in these blooms could also be passed to humans via shellfish to
cause a syndrome named
Symptoms & signs (neurotoxic shellfish
poisoning (NSP)) : tingling in the face, throat and digits, dizziness,
fever,
chills, myalgia, abdominal
pain,
nausea
and vomiting,
diarrhea,
headache,
bradycardia
and mydriasis.
There have been no reported fatalities from NSP, although BVX kills test
mammals when administered by various routes, including orally
There are about 30 recorded instances of people being killed by cone snails
— the molluscs are aggressive if provoked and can penetrate wetsuits with
their sharp poison-loaded harpoons, which look like transparent needles.
Human victims seem to suffer little painref,
because the venom contains an analgesic component. Today, the venom's painkilling
properties are just one facet of a burgeoning field of research and drug
development. The animals are difficult to keep in captivity. When popped
into a football sock, the snail draws it body into its shell and keeps
its harpoon out of harm's way. Australian scientists first separated cone
snail venom into its constituent parts in 1977ref.
Unlike most venomous animals, which produce one or a few poisons, a single
snail can produce up to 100 individual toxins. It now seems that the Conus
species will each use a distinctive assortment of peptides and that the
pharmacological diversity in Conus venoms may be ultimately comparable
to that of plant alkaloids or secondary metabolites of microorganisms :
further the snails produce different toxins at different times — possibly
influenced by external conditions such as temperature. The cone snails
may generate this diverse spectrum of venom peptides by a "fold-lock-cut"
synthetic pathway. These peptides are specific enough to discriminate effectively
between closely related receptor subtypesref
and can be used for structure-function correlations. The overuse of cone
snails for scientific research concerns conservationistsref.
In the wild, cone snail orgies allegedly occur, but no one knows what triggers
these erotic extravaganzas.
=> conotoxins
: most are fewer than 30 amino acids in length and require HPLC to be diffferentiated.
Milked toxins are subtly different from those that are extracted from the
venom glands of dead snails : the toxins are processed by enzymes as they
move down the venom duct. Different groups of conotoxins — most known by
various letters of the Greek alphabet — target other ion channels, such
as those for sodium and potassium, or receptors and transporters for neurotransmitters
such as glutamate, serotonin, neurotensin and noradrenalineref
a-conotoxin
Vc1.1 from Conus
victoriae binds to N AChR
and is in preclinical trials at Metabolic
for patients with diabetes who are suffering from the neuropathic pain
that is a complication of the disease
conotoxin MI is 2-3 times more active than the others, and presumed
to act as an acetylcholine receptor of vertebrate neuromuscular junctions.
conotoxin GS is an antagonists for voltage-gated
Na+ channels
from Conus
geographus. It exists as a single polypeptide chain, consisting
of 34 amino acid residues, cross-linked by 3 disulfide bonds. Its amino
acid sequence was shown to be Ala-Cys-Ser-Gly-Arg-Gly-Ser-Arg-Cys-Hyp-Hyp-Gln-Cys-Cys-Met-Gly-Leu-Arg-
Cys-Gly - Arg-Gly-Asn-Pro-Gln-Lys-Cys-Ile-Gly-Ala-His-Gla-Asp-Valref
MVIIA from Conus
magus is an irreversible, specific blocker of N-type
calcium channels,
causes tremors in mice and is in phase III clinical trials at Elan®
for cancer pain as an intrathecal analgesic. As the channel that has been
implicated in chronic neuropathic pain, caused by damage to the nervous
systemref,
the toxin has since been developed as a synthetic drug called ziconotide
/ SNXIII (Prialt®) and is now in advanced clinical trials
for patients with cancer and AIDS who are suffering from pain
that cannot be relieved by opiatesref.
contulakin-G, a 16-amino acid O-linked
glycopeptide (pGlu-Ser-Glu-Glu-Gly-Gly-Ser-Asn-Ala-Thr-Lys-Lys-Pro-Tyr-Ile-Leu-OH,
pGlu is pyroglutamate), from Conus
geographus. The major glycosylated form of contulakin-G was found
to incorporate the disaccharide b-D-Galp-(1-->3)-a-D-GalpNAc-(1-->)
attached to Thr10. The C-terminal sequence of contulakin-G shows a high
degree of similarity to the neurotensin family of peptides. It is in phase
II clinical trials at Cognetix®
for chronic painref.
It is an agonist on neurotensin
receptor 1
and neurotensin receptor 2
conantokins are small peptides (17-27 amino
acids) that act as NMDAR
antagonists. Unlike most of the peptides characterized from cone snail
venom that contain multiple disulfide bridges, conantokins are linear peptides
that possess a high degree of a-helicity in
the presence of divalent cations, and contain g-carboxyglutamic
acid residues. The conantokins have been synthesized and characterized
in a number of animal models of human pathologies including pain, convulsive
disorders, stroke, and Parkinson's disease
conantokin-G (conG) from Conus
geographus is selective for subtypes of NMDARs containing the NR2B
subunit and is in preclinical trials at Cognetix®
for epilepsyref
conantokin-T (conT) from Conus
tulipa is selective for subtypes of NMDAR containing NR2A and NR2B
subtypesref
conotoxin TVIIA a 30-residue polypeptide
extracted from Conus
tulipa. TVIIA contains six cysteine residues which form a '4-loop'
structural framework common to many peptides from Conus venoms including
the v-, d-, k-,
and mO-conotoxins. However, TVIIA does not belong
to these well-characterized pharmacological classes of conotoxins, but
displays high sequence identity with conotoxin GSref1,
ref2.
contryphan-Vn is a modulator of Ca2+-dependent
K+ channels (KCa) extracted in 2001 from Conus
ventricosus. As with other contryphans, Contryphan-Vn contains
a d-tryptophan residue, is amidated at the C-terminus, and maintains the
five-residue intercystine loop size. However, Contryphan-Vn differs from
the known contryphans by the insertion of the Asp residue at position 2,
by the lack of hydroxylation of Pro(4), and, remarkably, by the presence
of the basic residue Lys(6) within the intercystine loopref
=> kahalalide F (KF) is a DNA-binding
cyclic depsipeptide that covalently interacts with the minor groove of
the DNA double helix to bend the molecule towards the major groove.
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