PRINCIPLES OF TOXICOLOGY

which primarily stimulate certain serotonin receptors in the brain. Finally, several mushrooms
synthesize ibotenic acid, a potentially neurotoxic glutamate receptor agonist similar to domoic
acid.
In addition to the mushrooms, there are other toxic fungi. Ergot is a fungus that grows upon certain
grains in damp climates. This fungus produces a variety of biogenic amines which act as agonists on
alpha-type adrenergic receptors including ergotamine, which is used therapeutically to treat migraine
headaches. Methysergide, a serotonin antagonist, is probably the major hallucinogenic component of
ergot. Some molds have been found to produce carcinogenic substances called aflatoxins and
ochratoxins; proper storage of vegetable crops susceptible to these molds eliminates conditions
favorable for their growth.
Flowering Plants
17.6 TOXINS OF HIGHER PLANTS 419
Cardiac Glycosides and Saponins Cardiac glycosides are animal as well as plant products. The
traditional source of these compounds for medicinal use in the West has been the foxglove, a
beautiful flowering plant (Figure 17.4) now extensively cultivated in many countries. The major
glycosides of the foxglove are called digitoxin and digoxin. In the Orient, toad venom glands were
used as a major source of very similar medicinal compounds (bufotoxins). The primary therapeutic
use of digitalis glycosides is the treatment of congestive heart failure, a condition characterized
by a loss of myocardial contractility. For various reasons (including long-term hypertension,
atherosclerosis, kidney failure, etc.), the heart is unable to pump the blood sufficiently to avoid
its pooling in the lungs and extremities.
Over 300 years ago, Withering found that the leaf of the foxglove was very effective in treating this
condition, then known as dropsy. Unfortunately, digitalis glycosides are also amongst the most toxic
of drugs, frequently causing cardiac arrhythmias at concentrations required to significantly enhance
the cardiac output. The site of their action is the sodium, potassium pump (also known as the
Na,K-activated Mg-ATPase) in the cell membrane. This active transport system is responsible for
maintaining the high potassium, low-sodium intracellular environment of all cells. However, in the
heart it appears that blockade of a fraction of the pumping sites with digitalis allows the intracellular
sodium concentration to transiently rise above normal during each myocardial action potential, and
this elevated sodium then is exchanged with calcium from outside the cell by a membrane carrier called
the sodium–calcium exchanger. This causes elevation in the intracellular calcium during the heart beat,
which stimulates the actomyosin system to contract more forcefully. It is quite remarkable that these
glycosides can be used as inotropic drugs at all, considering that all cells possess sodium, potassium
pumps which are inhibited by digitalis.
Other plants (Table 17.3) that produce dangerous quantities of digitalis compounds are the oleander
bush (Nerium), which is an extremely common ornamental shrub in the southeastern United States,
the lily-of-the-valley (Convallaria) ornamental flower, and a wildflower, the butterfly weed (Asclepias).
A single oleander leaf contains enough cardiac glycoside to be lethal to an adult human. The
danger with foxglove is that during the nonflowering season its leaves are confused with those of the
common comfrey plant, whose leaves are popularly used in the preparation of herbal teas. This has led
to several deaths due to inadvertent use of foxglove leaves.
Toxic saponins are found in potato spuds, green tomatoes (major saponin, α-tomatine), and other
members of the family Solanaceae. They are also produced by sea cucumbers and starfish. Many
saponins are capable of disrupting the normal bilayer packing of phospholipids in cell membranes,
and this may cause the affected cells to become abnormally leaky to ions, ultimately bringing about
lysis (cell death). The major saponin present in foxglove is called digitonin; it is an extremely active
detergent.
Ginseng (Panax) is a traditional herbal medicine supposedly useful for a wide variety of ailments,
including fatigue, sexual impotency, heart disease, and even cancer. The ginseng root contains large
amounts of saponins called glycyrrhizins. These natural products are apparently safe when adminis-