PRINCIPLES OF TOXICOLOGY

17.4 MAJOR SITES AND MECHANISMS OF TOXIC ACTION 413
(including the South American Indian arrow poison tubocurarine and certain snake venom toxins) that
reversibly bind to the same site without activating it are competitive antagonists. Besides the ACh
recognition site, there are other places on this large membrane protein complex at which toxins can
act. For instance, many small alkaloid toxins can enter the ion channel and physically plug it! Other
toxins probably bind at the interface between the polypeptide subunits and the adjacent lipid bilayer
(Figure 17.1b).
The muscle cell membrane, continuous with the postsynaptic membrane of the muscle cell, is
electrically excitable and must be able to generate an action potential in response to the ACh-induced
depolarization. An action potential involves the sequential opening and closing of two different ion
channels in response to membrane depolarization. First, the sodium-selective channel opens; sodium
ions flow into the cell, reversing its electrical potential so that the inside of the cell momentarily
becomes electropositive. This causes the adjacent membrane to be depolarized, which, in turn, activates
the opening of more sodium channels. In this manner, a wave of electrical change rapidly passes along
the length of the muscle fiber. This depolarizing wave is quickly followed by a repolarizing wave due
to the opening of potassium ion selective channels, which allows potassium to flow out of the cell,
down its concentration gradient. It is counterproductive for the sodium channels to remain open while
potassium channels are opening, so an additional process called sodium channel inactivation takes
place during the opening of the potassium channels. In some muscle cells, a calcium-selective channel
either substitutes for the sodium channel (in smooth muscle) or supplements its ability to depolarize
the cell (in cardiac muscle).
In smooth muscles and many neurons, voltage-gated calcium channels substitute for sodium
channels in causing at least part of the initial cationic influx, which generates action potentials. At
nerve terminals, calcium ions flowing through these calcium channels also mediate the exocytotic
release of neurotransmitter. There are several extremely potent toxins that activate or inhibit these
calcium ion-passing channels, which we will discuss later. There are even intracellular calcium
channels within muscle cell sarcoplasmic reticulum membranes, which must be able to quickly release
calcium ions for muscle contraction; these calcium channels can be blocked by a plant toxin called
ryanodine.
Every ion channel seems to be a potential target for some natural toxin, which usually acts at a
much lower concentration than do drugs acting on the same site. For instance, one of the most potent
local anesthetics, tetracaine, blocks sodium channels of nerve at concentrations above 10 –6 M, whereas
the pufferfish toxin tetrodotoxin achieves the same blockade at a thousand-fold lower concentration!
There are at least seven different sites on sodium channels where toxins act; some of these are listed
in Table 17.2.
Cardiovascular Toxins
The cardiovascular system is also quite vulnerable to many natural toxins that act on ion channels in
cardiac or smooth muscles or on autonomic nerve terminals. Many lethal actions of venoms probably
are due to rapid action on these excitable cells. Once the victim is envenomated, the active
constituents spread locally according to their molecular size and other chemical properties. Their
entry into the systemic circulation will be greatly enhanced if they rapidly spread into tissues
surrounding the bite; this can be enhanced by a venom enzyme, hyaluronidase, which breaks down
the hyaluronic acid in connective tissue. Some venoms also contain hemorrhage-inducing,
anticoagulant, and hemolytic proteins, which together can cause much loss of blood volume, tissue
oedema, and cytolysis. Thus the cardiovascular system can be affected in many different ways by
venoms and their toxic constituents.
Toxins Affecting the Liver and Kidneys
Two other organs that are especially vulnerable to toxins are the liver and the kidney. The hepatic portal
venous system first delivers substances absorbed from the gastrointestinal tract to the liver. This organ