PRINCIPLES OF TOXICOLOGY

could be at least partially achieved by reducing postsynaptic membrane responsiveness to ACh with
nicotinic and muscarinic receptor antagonists. This potential method of treatment could supplement
the use of antivenins.
Spiders generally poison their insect prey. Fortunately, vertebrate nervous system receptors are
pharmacologically different enough from those of insects that most spider toxins are not very active
on humans. It also helps that we are so big and their normal prey and predators are so small!
Nevertheless, several spiders are exceedingly dangerous. Black widow spiders (Latrodectus sp.) occur
throughout the world, so we shall consider them first. Their venom is primarily neurotoxic due to the
presence of a powerful protein toxin called alpha-latrotoxin (Table 17.1). This large protein enhances
neurotransmitter release from nerve terminals, and can even cause nerve terminal secretory vesicle
depletion. Victims concurrently suffer from skeletal muscle spasms and autonomic overstimulation
(causing sweating, salivation, nausea, and hypertension). Again, treatment is primarily based upon
administration of Latrodectus antivenin. Some relief from these symptoms can be achieved with
centrally acting muscle relaxants like diazepam, and autonomic overstimulation can be ameliorated
with muscarinic and/or adrenergic antagonists, depending on the symptoms.
Brown recluse spider venom (Loxoceles sp.) acts in an entirely different way because its venom
primarily contains an enzyme, sphingomyelinase, which causes tissue damage. While this venom is
less dangerous than black widow venom, it can cause significant tissue necrosis at the site of the bite.
Although the bees, hornets, and wasps all belong to the order Hymenoptera, their venoms are
different. The most serious reactions to hymenopteran stings are of the immediate hypersensitivity
type and are due to an immune response from previous stings mediated by immunoglobulin E. Bee
venom has been found to be an exceedingly rich mixture of enzymes and toxins. The primary enzyme
of importance is phospholipase A, which acts synergistically with a peptide detergent called mellitin
(named after the common honeybee Apis mellifera) to break down phospholipids in the plasma
membrane, thereby liberating prolytic fatty acids and lysolecithin. While mellitin can act alone to
disrupt the cell membrane, its action is greatly facilitated by the presence of these phospholipid
breakdown products. Like many snake venoms, bee venom also contains the enzyme hyaluronidase,
which breaks down connective tissue and thus facilitates the spreading of the venom from its site of
injection. Bee venom also contains two peptide toxins, apamin and mast cell degranulating peptide,
which respectively block calcium-activated and voltage-activated potassium channels.
In contrast to bee venom, the wasp and hornet venoms primarily contain small peptides called kinins
which, like our endogenous bradykinin, have a triple action: stimulation of sensory nerve endings
resulting in neurogenic inflammation, increased capillary permeability, and relaxation of vascular
smooth muscle.
Fire ants (Solenopsis) are quite abundant in the southeastern United States, and many people are
stung each year. The venom contains piperidine alkaloids, which have been found to block the nicotinic
receptor ion channel. Protein constituents are thought to be at least partly responsible for the painful
sensation associated with the sting. Irritating pustules and some minor tissue necrosis may result at the
sting, extending the period of discomfort to several days. The role that the alkaloids (called solenopsins)
play in the inflammatory responses associated with fire ant stings is not entirely clear, but solenopsins
are known to cause histamine release from basophils.
Mollusc Venoms and Toxins
17.7 ANIMAL VENOMS AND TOXINS 427
The molluscan exoskeleton provides considerable protection against predators but also limits mobility.
This poses a problem for predatory snails. However, one group of gastropods called “cones” possesses
a formidable harpoon-like venom apparatus for paralyzing its prey. Conus venom was extensively
investigated in the 1990s. Almost all Conus toxins are peptides or small proteins. The venom is a virtual
cocktail of ion channel modulators including nicotinic receptor antagonists (α-conotoxins), sodium
channel blockers (µ-conotoxins), calcium channel blockers (ω-conotoxins), and glutamate channel
blockers (conantokins). Only a relatively small fraction of the 300 known species of Conus are