PRINCIPLES OF TOXICOLOGY

stimulates various phosphoryl kinase enzymes, which catalyze the phosphorylation of ion channels
and other signaling systems, thereby modulating their function. Several toxins have been found to
specifically alter the cAMP-generating system. Some act indirectly by affecting guanosine nucleotidebinding
(so-called G) proteins, which modulate adenylate cyclase. For instance, cholera toxin stimulates
Gs (the stimulatory G protein subunit) formation and therefore enhances cAMP synthesis, while
pertussis toxin inhibits binding of the inhibitory G protein subunit Gi to the cyclase and thereby also
stimulates cAMP synthesis (Figure 17.2). The sponge toxin okadaic acid acts in an entirely different
fashion, inhibiting certain phophatases that normally reverse the cAMP-catalyzed phosphorylation,
and this leads to an enhancement in cAMP concentration.
Inflammatory and Carcinogenic Toxins
These types of toxins are usually meant to discourage consumption or even contact with the toxic
organism. Many sedentary organisms like plants and some marine animals synthesize inflammatory
substances. These may be similar to endogenous chemical mediators, such as histamine, prostaglandins,
or phospholipids, or may liberate the endogenous mediators from basophils and other cells
mediating inflammatory processes.
Some of the most potent carcinogens are natural substances, like the ochratoxins. In many cases
their mechanisms of action are not yet known. Ames has presented the provocative hypothesis that the
dangers of exposure to some industrial carcinogens may not be any greater than the risks associated
with daily consumption of small amounts of natural carcinogens occurring in some food plants.
17.5 TOXINS IN UNICELLULAR ORGANISMS
Bacterial Toxins
17.5 TOXINS IN UNICELLULAR ORGANISMS 415
There are so many bacterial toxins that we are here forced to consider only a few of the most common
and interesting ones. In fact, the most potent natural toxins are bacterial protein neurotoxins (Table
17.1).
Botulinum poisoning is primarily a foodborne disease, which can develop when food is improperly
canned, allowing anaerobic Clostridium botulinum bacterial spores to survive and multiply. There are
several strains of this anaerobe that synthesize related toxins. All botulinum toxins act by inhibiting
neurotransmitter release at the skeletal muscle neuromuscular junction (Figure 17.1a). This peripheral
action is dominant with botulinum toxins and leads to flaccid paralysis and eventually death if unabated.
Treatment is difficult. After binding, toxin is internalized at the motor nerve terminal, and then acts
internally. Botulinum antiserum can neutralize toxin that has not yet been internalized. Neuromuscular
transmission may be enhanced by treating the patient with an acetylcholinesterase inhibitor such as
neostigmine. Artificial respiration may be necessary until the patient regains new transmitter release
sites.
Tetanus poisoning is due to another anaerobe, Clostridium tetani. Again, several strains form related
toxins. Although they all act to inhibit neurotransmitter release in a manner superficially similar to
botulinum toxin, the tetanus toxins in mammals predominantly inhibit the release of an inhibitory
neurotransmitter, glycine, within the central nervous system. This inhibition of an inhibitory influence
(called “disinhibition”) on central motor neurons permits full expression of the excitatory synaptic
input to these neurons, causing peripheral excitation of all skeletal muscles. Since extensor muscles
are usually most powerful, victims may become immobilized in a contorted contraction that is
life-threatening. “Lockjaw” is only symptom of this condition. Most of us are vaccinated with tetanus
toxoid as children, so the likelihood of developing tetanus poisoning is greatly reduced; a “booster”
vaccination should also be taken about every 10 years, particularly for various outdoors persons who
are more likely to be exposed to this bacterium (gardeners, farmers, trash handlers, etc.).