Page 517 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

484 SECTION | V Metals and Micronutrients

VetBooks.ir PHARMACOKINETICS/TOXICOKINETICS undergoes hepatic metabolism to sulfate, which is elimi-
nated in the urine (NRC, 2006).
When evaluating the absorption of sulfur, the chemical
form must be considered. The intestinal mucosal absorp-
tion of sulfate is via an active carrier-mediated process MECHANISM OF ACTION
that is also utilized by molybdate (Mason and Cardin,
Acute oral poisoning with elemental sulfur results in the
1977). Active intestinal absorption of sulfate has been
formation of hydrogen sulfide, as well as many other
shown in sheep, rats, dogs, rabbits, and hamsters (Bird
potential metabolites. The gastric and respiratory effects
and Moir, 1971). Similarly, the sulfur-containing amino
are postulated to be due to the coagulative effects of
acids and other sulfur-containing compounds are absorbed
rumen-produced sulfurous acids and the irritating effects
via specific transporter mechanisms across the intestinal
of hydrogen sulfide, respectively (Julian and Harrison,
mucosa (NRC, 2006). These specific transport processes
1975; Kandylis, 1984; Gunn et al., 1987). However, the
are specific for the individual compounds. Rumen
exact mechanisms are not well delineated. Inhaled rumi-
microbes convert a percentage of dietary sulfur-
nal sulfide at high concentrations may act in a similar
containing compounds to sulfide, which can then be
mechanism to high concentrations of exogenous hydrogen
incorporated into microbial sulfur-containing amino acids,
sulfide gas, causing acute respiratory paralysis.
thiamine, biotin, other microbial sulfur metabolites, or
The mechanism of subacute sulfur poisoning has been
absorbed as sulfide. In addition to gastrointestinal absorp-
more extensively researched. This condition is correlated
tion of sulfides, hydrogen sulfide can be absorbed across
with the reduction of the sulfate or other forms of sulfur
respiratory epithelium. Large amounts of sulfide, as
to sulfide in the rumen (Gould et al., 1991, 1997;
hydrogen sulfide, produced in the rumen can be eructated,
Loneragan et al., 1998). The current literature suggests
inhaled and absorbed (Dougherty et al., 1965). Inhaled
that inhibition of cytochrome C oxidase, which is essen-
sulfide is important in sulfur toxicosis, as sheep that had
tial for cellular respiration, is the primary mechanism of
their trachea blocked to prevent eructation and inhalation
poisoning (Smith et al., 1977; Beauchamp et al., 1984).
of sulfide did not succumb while those without tracheal
However, cerebral vasospasms and regional ischemia
block were poisoned (NRC, 2006).
could also account for the localization of the lesions
Sulfur is widely distributed in the body. All tissues in
(Siesjo, 1984; McAllister, 1991). Although once thought
the body have significant sulfur components, with the
to be associated with a true thiamine deficiency from
body being made up of approximately 0.15% sulfur
either inhibition of rumen microbial production or cleav-
(NRC, 2006). Absorbed sulfides and thiomolybdates, the
age of thiamine (Edwin and Jackman, 1982), it has been
primary toxic sulfur metabolites, are well distributed in
shown that systemic thiamine concentrations are within
the body. This is evidenced by the fact that thiomolybdate
the normal range for most animals (Olkowski et al., 1992;
can deplete tissue stores of copper, and sulfides can cross
Gould, 2000). However, more recent research has impli-
the blood brain barrier causing neurological effects.
cated low brain concentrations of thiamine pyrophos-
Sulfur-containing amino acids and sulfate are exten-
phate, one of the biologically active forms of the vitamin
sively metabolized in order to produce biologically uti-
that is important in several metabolic pathways (Amat
lized sulfur compounds. In comparison, absorbed sulfide
et al., 2013). A slight decline in the blood thiamine con-
is efficiently metabolized in the liver to sulfate, with a
centration can also be seen in some animals (Olkowski
high first pass clearance (NRC, 2006). Inhaled sulfide
et al., 1991). However, thiamine supplementation in the
would not be subject to the rapid hepatic removal that
presence of high sulfate/sulfur-associated PEM suppresses
occurs for that absorbed from the gastrointestinal tract.
the clinical disease (Olkowski et al., 1992). This would
This results in increased circulating concentrations that
indicate that the sulfide or some other sulfur metabolite is
can expose neuronal tissues and result in toxic neurologic
either competitively inhibiting the cellular uptake/utiliza-
effects.
tion of thiamine, or therapeutic doses of thiamine dimin-
Sulfur-containing compounds are eliminated by both
ish the effects of sulfide on the cytochrome C oxidase
renal and biliary routes. Just as molybdate can compete
enzyme.
for the intestinal absorption sites for sulfate, it can also
The subacute to chronic, indirect effects of excessive
compete for reabsorption sites in the renal tubules
sulfur are seen in ruminants, due to the efficient conver-
(Friberg and Lener, 1986). The relative quantities of sul-
sion of sulfur compounds to sulfide. The sulfide can form
fur elimination from renal and biliary routes can differ
insoluble salts with copper and zinc (Suttle, 1974), but it
depending on the form ingested. In sheep, Bird (1972)
can also react with molybdenum and form thiomolybdate
found the greatest percent elimination of sulfate was via
complexes, which efficiently bind copper making it
urine, while that from taurine was predominantly elimi-
nonbioavailable (Suttle, 1991). Systemic copper
nated in the bile. Intestinally absorbed sulfide efficiently
decreases, associated with increased sulfur/sulfate, have