PRINCIPLES OF TOXICOLOGY

426 PROPERTIES AND EFFECTS OF NATURAL TOXINS AND VENOMS
Ciguatoxin (Table 17.2), which activates voltage-gated sodium channels in nerve and muscle cells,
is a prime example. Ciguatera poisoning is quite unpredictable; the predatory fish is edible most of the
time in a particular place. It causes a variety of symptoms such a lethargy, tingling and numbness of
the lips, hand and/or feet weakness, itching, joint pains, and gastrointestinal symptoms including
diarrhea. These problems may last up to several months because this lipophilic toxin is eliminated very
slowly. It is active in such minute concentrations that research on its structure was hampered for over
a decade because insufficient amounts were available for analysis. Ciguatera infestations occur in the
Carribean Sea as well as in the tropical Pacific. The symptoms differ in these sites, suggesting that the
toxins are not exactly the same. Administration of hyperosmotic mannitol seems to be an effective
symptomatic therapy for controlling the Schwann cell edema caused by this complicated molecule.
Arthropod Toxins and Venoms
This animal phylum consists of such different animals as scorpions, spiders, and insects. Many
arthropods use neuroactive substances as repellents, alarm pheromones, or as toxins. While the insects
are the largest group in terms of biodiversity, only a small proportion of species seem to possess toxins,
whereas almost all scorpions and spiders routinely use venomous secretions to capture their prey and
deter predators. Fortunately for us, most arthropod toxins have evolved in the direction of immobilizing
animals other than mammals. Only a relatively small group of spider species are known to be poisonous
to humans.
Scorpion venom is one of the richest sources of peptide toxins known; it is comparable in diversity
to the cone shell venoms, which will be described in the next section. Scorpions quickly immobilize
their prey, generally insects, by injecting a complex mixture of peptides that act on the voltage-gated
sodium and potassium channels, which then produce action potentials. There are two kinds (called
alpha and beta) of toxins, that bind at sites 3 and 4, respectively, on the external surface of the sodium
channel (Table 17.2). Both enhance electrical excitability by modulating the probability that the sodium
channel will remain open, even when the electrical potential of the membrane is nearly the same as in
the resting state (about 60–90 mV negative on the inside surface of the membrane).
The α-scorpion toxins specifically slow a process, referred to as inactivation, by which the open
sodium channel turns off in the presence of membrane depolarization. A normally brief (duration about
one millisecond) action potential is turned into an abnormally long signal whose duration may be
several hundred milliseconds. This causes a massive release of neurotransmitters at peripheral nerve
terminals on skeletal and other muscles. The consequences for the victim are disastrous, namely
hyperexcitability, convulsions, paralysis, and sometimes death. The β-scorpion toxins by a different
mechanism also cause peripheral nervous system hyperexcitability by stimulating the nerves and
muscles to generate trains of multiple action potentials in response to each depolarizing stimulus. The
β-scorpion toxins reduce the rate at which the opened sodium channel returns to its resting state, a
process often referred to as “deactivation.” Old-world scorpions generally contain only the alpha-type
sodium channel toxins, whereas the new-world species often contain both α- and β-neurotoxins.
Antivenins are available for the most dangerous scorpions and offer the most effective means of
treatment.
Since the late 1980s, another group of smaller peptide toxins, which block various potassium
channels, has been discovered in scorpion venoms. Since the electrical excitability of a nerve or muscle
cell at any instant depends on the relative permeability of the membrane to sodium and potassium ions,
it makes good sense for a scorpion venom to also contain toxins that block potassium channels.
Charybdotoxin, the first of these toxins to be characterized, primarily blocks calcium-activated
potassium channels found in smooth and skeletal muscles. This channel protects the cell against
excessive membrane depolarization and internal calcium loading. Charybdotoxin also blocks some
voltage-activated potassium channels in the brain.
Because of this multiplicity of toxins in scorpion venom that enhance electrical excitability, an
alternative approach for treating scorpion envenomation would be to reduce excitability, particularly
in the peripheral nervous system (these peptides do not readily cross the blood–brain barrier). This