PRINCIPLES OF TOXICOLOGY

416 PROPERTIES AND EFFECTS OF NATURAL TOXINS AND VENOMS
+NT
RS
GS
GTP
Bγ
αS
αS
GTP
GDP
CT
AC
+ –
ATP
ADP
Cytotoxic proteins produced by infectious bacteria frequently contribute to the fever, vasodilation,
and tissue damage associated with infection. Staphylococcal alpha toxin is one of the best understood
representatives of this group. Several molecules of this toxin aggregate together on the target cell
membrane and form a large pore allowing release of various cellular constituents, even large proteins.
Cytolytic toxins are rarely lethal, although they contribute to the symptoms of bacterial infection.
Cholera toxin (Fig. 17.2) activates G S protein coupling to adenylate cyclase. This stimulates
intestinal ion and water secretion and results in dehydration and death if not properly treated.
Other bacterial cytotoxins act in an entirely different manner by inhibiting protein synthesis in the
target cell. Diphtheria and Pseudomonas toxins are good examples. It has been calculated that a single
molecule of one of these toxins is sufficient to inhibit enough protein synthesis that the cell cannot
replenish the proteins that are also being continuously broken down. Fortunately, however, the process
by which the cytotoxin is internalized and gains entry into the cytoplasmic compartment is not so
efficient; it actually takes thousands of cell membrane-bound toxin molecules to result in one molecule
lethally reaching its ribosomal destination.
Many bacteria are practically ubiquitous because their spores are widely distributed by air and water
movements around the earth. However, some species have a much more localized distribution. One
example is the marine bacterium Vibrio vulnificus, which can cause life-threatening infections in
persons who consume raw marine shellfish or swim in the sea with skin abrasions that are vulnerable
to infection. In a recent study many patients developed necrotic tissue or liver disease; about 20 percent
died. A 56 kilodalton cytolytic protein called vibriolysin is thought to mediate the tissue damage.
Although the alkaloidal neurotoxin tetrodotoxin was originally thought to be synthesized only by
pufferfish and certain newts (amphibians), in the past decade it has been found in a wide variety of
marine animals including worms, crabs, and an Australian octopus. Since tetrodotoxin was recently
found to be synthesized by several species of marine bacteria, it is likely that the animals obtain the
toxin from microbial symbionts.
A Toxin Implicated in Amebic Dysentery
Gi
GDP PT
CAMP
Infection by a freshwater amoeba, Entamoebae histolytica, can cause life-threatening meningitis in
addition to inflammation of the colon and intestinal abscesses. Tissue damage only occurs on direct
–NT
Ri
+
PK-A
ATP
+
+
Pi
Ca ++
–
Pi
PP
OA
Figure 17.2 Control of adenylate cyclase (AC) by toxins affecting G proteins. Initially, stimulatory (+NT) or
inhibitory neurotransmitters interact with their respective receptor proteins, which are indirectly coupled to AC
through different G proteins. Cholera toxin (CT) enhances cyclic AMP production by enhancing the interaction of
stimulatory GS protein with the adenylate cyclase, while pertussis toxin (PT) enhances cyclase activity by inhibiting
the interaction of the inhibitory GI protein with another site on the cyclase. A sponge toxin, okadaic acid (OA),
enhances cyclic AMP action by an entirely different mechanism, namely, by inhibiting certain phosphatase