Page 1024 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

956 SECTION | XIV Poisonous Plants

VetBooks.ir (Faulstich and Fauser, 1980). The bioavailability of ama-
nitins appears to be much greater in humans than in
rodents, dogs, and rabbits. Within animal species, the
absorption rate of amanitins is estimated to be much
greater in dogs than in mice and rabbits, and rats appear
resistant to the toxic effects of amanitins. α-Amanitin is
taken up by cells in the gastrointestinal tract, where the
first damaging effects are seen (Gundala et al., 2004).
Following systemic absorption, α-amanitin is taken up by
hepatocytes via OATP1B3, an organic anion-transporting
polypeptide (Letschert et al., 2006). The α-amanitin has a
low volume of distribution. Renal clearance is high and
rapid, and similar to the creatinine clearance (Faulstich
et al., 1985). Following intravenous (i.v.) administration
in dogs, it was shown that plasma half-life of amanitins is
FIGURE 67.2 Amanita ocreata. Courtesy of Dr. R. Michael Davis, short, ranging from 25 to 50 min, and that amanitins are
University of California at Davis. not detectable in plasma after 4 6 h. In pigs following
intraportal administration of α-amanitin, systemic plasma
several characteristics: a smooth, yellowish-green to and portal plasma amanitin concentrations declined to
yellowish-brown cap; white gills; a white ring around baseline levels within 24 h (Thiel et al., 2011). There is
the upper part of the stem (veil); and a white cuplike no known metabolism or plasma protein binding of the
structure (volva) around the base of the stem. Amanita α-amanitin. Between 80% and 90% of the administered
ocreata (Fig. 67.2) is commonly known as western North dose of amanitins is eliminated in urine, and up to 7% is
American destroying angel and grows from Baja eliminated in bile (Faulstich et al., 1985). After oral
California, Mexico, along the Pacific Coast to Washington. ingestion of A. phalloides in humans, α- and β-amanitins
A. ocreata is most commonly found in sandy soils under were detected in plasma up to 36 h after ingestion and in
oak or pine and has caused fatalities in dogs (B. Puschner, urine up to 72 h postexposure (Jaeger et al., 1993). This
unpublished data). The fruiting bodies are usually found in may partly be due to slow intestinal absorption, enterohe-
late winter and spring. A. ocreata has a white or cream- patic circulation, and reduced renal elimination resulting
colored cap; white, short gills; a white stem with a from nephrotoxicity. Plasma and urine amanitin concen-
white, thin, broken, partial veil (annulus); and a white, trations do not seem to correlate with the clinical severity
thin volva. Amanita bisporigera, Galerina autumnalis, or outcome.
and Lepiota josserandii have also been attributed to ani- Amanitins can be detected in serum and urine well
mal and human deaths in North America (Beug, 2009). before any clinical sign of poisoning, whereas routine lab-
In Eastern Europe, G. sulpices is considered the species oratory tests such as complete blood count and serum
most commonly associated with human fatalities, fol- chemistry profiles are unremarkable until liver or kidney
lowed by A. phalloides (Klan, 1993). There are three damage has occurred. Early recognition of exposure is
groups of cyclopeptides: the amatoxins, phallotoxins, critical because survival rates are greatly improved with
and virotoxins. Amatoxins are bicyclic octapeptides and timely therapeutic intervention. Amanitin concentrations
include the amanitins (α-, β-, γ-, and ε-amanitins), ama- in kidneys and livers of people ingesting A. phalloides
nin, amanullin, and proamanullin (Vetter, 1998). Severe have been detected up to 22 days postingestion. The kid-
poisonings and lethality are mainly attributable to the neys contain higher concentrations than the liver, indicat-
amanitins. The bicyclic heptapeptides phallotoxins were ing that toxins are bound to renal tissue.
once thought to be the cause of gastrointestinal clinical
signs; however, they are no longer believed to exert any MECHANISM OF ACTION
acute toxicity. Although research is limited, bicyclic
heptapeptides virotoxins are not considered to have Amanitins are of greatest significance because, unlike
toxic effects after oral exposure. Therefore, phallotoxins phalloidins, they are heat stable and are not degraded by
and virotoxins are not discussed further. the acid environment of the stomach or by freezing
(Himmelmann et al., 2001). Therefore, amanitins are toxic
by ingestion, whereas phalloidins have only been shown
PHARMACOKINETICS/TOXICOKINETICS
to be toxic when experimentally administered by paren-
Exact data on the bioavailability for amanitins are lack- teral routes. Amanitins exert their toxicity by inhibiting
ing, although there are known species differences nuclear RNA polymerase II (Lindell et al., 1970;