Page 497 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

464 SECTION | V Metals and Micronutrients

VetBooks.ir administered into the rumen of sheep appeared in the Mo, it can also compete for reabsorption sites in the renal
tubules and enhance the rate of elimination (Friberg and
plasma within minutes (Kelleher et al., 1983). The muco-
Lener, 1986).
sal absorption of molybdate is via an active carrier-
mediated process that is also utilized by sulfate (Mason
and Cardin, 1977). Absorption is quite efficient, ranging
MECHANISM OF ACTION
from 40% to 90% (Friberg and Lener, 1986; Turnlund
et al., 1995). However, Mo absorption does not appear to The mechanism by which Mo is active in biological sys-
be regulated at the point of mucosal absorption, as increas- tems is through its redox activity in functional molybdo-
ing Mo concentrations presented to the mucosa result in enzymes (Mills and Davis, 1987). The readily changeable
concomitant increased absorption (Miller et al., 1972; oxidation states of Mo lend it to functional utilization in
Turnlund et al., 1995). these types of reactions.
Dietary constituents can limit Mo absorption. Dietary The primary mechanisms by which Mo is toxic are
sulfate present at the point of absorption can competi- directly tied to its interactions with sulfur and copper.
tively inhibit molybdate uptake (Mason and Cardin, These interactions result in overt or functional copper
1977). Furthermore, in the presence of sulfur/sulfates, the deficiency, including inhibition of copper dependent
reductive rumen metabolism results in di-, tri-, and tetra- enzyme systems. However, these interactions differ sig-
thiomolybdates, which can then bind copper and form a nificantly among species, with ruminants being much
nonabsorbable cupric thiomolybdate complex (Dick, more susceptible than monogastrics, due to the ruminal
1956; Price et al., 1987; Gooneratne et al., 1989). production of thiomolybdates. The reducing environment
of the rumen converts sulfate or sulfur from sulfur-
containing amino acids to sulfide, which then forms
Distribution
mono-, di-, tri-, and tetra-thiomolybdates (Price et al.,
Mo is widely distributed in tissues but has highest con- 1987; Spears, 2003). Thiomolybdates’ binding of copper
centrations in the liver, kidney, and bone (Schroeder in the digestive tract prevents absorption of ingested cop-
et al., 1970; Friberg and Lener, 1986). In light of the per, while systemic binding renders it nonbioavailable for
essential nature of Mo, it is somewhat unusual that very tissue utilization (Gooneratne et al., 1989; Suttle, 1991).
little tissue retention/reserve is maintained. Postabsorptive These cupric thiomolybdate complexes also result in
circulation occurs by transport bound to the red blood cell enhanced copper excretion (Howell and Gooneratne,
proteins or as free ionic molybdate (Allway et al., 1968; 1987). Price et al. (1987) found that the ruminal binding
Versieck et al., 1981). However, absorbed or systemically was predominantly via tri- and tetra-thiomolybdates,
produced thiomolybdates can bind copper and result in while systemic effects were predominantly via di- and tri-
circulating copper thiomolybdate complexes which are thiomolybdates. In practical terms, the thiomolybdates
not biologically available for tissue utilization. Some of serve as effective chelators of copper, preventing copper
the circulating or tissue thiomolybdates may also be absorption and depleting functional body stores. As the
bound to copper dependent enzyme systems, resulting in rumenal microbial populations can differ significantly
functional inhibition (Gould and Kendall, 2011). among ruminant species, the relative sensitivity among
species could be related to the overall conversion to thio-
Elimination molybdates or the relative abundances of the mono-, di-,
tri-, and tetra-thiomolybdates produced.
Mo is eliminated from the body fairly rapidly, with little, Most of the clinical syndromes of Mo poisoning can
and only short-term, tissue retention. Although urinary is be tied to deficiencies in copper-containing enzyme sys-
the primary route of elimination, biliary elimination also tem functions via overt deficiencies (NRC, 2006) or inhi-
occurs (Friberg and Lener, 1986; Vyskocil and Viau, bition of enzyme systems (Gould and Kendall, 2011).
1999; NRC, 2006) and likely is the primary route of elim- Although most clinical effects of Mo poisoning are
ination in ruminants (Grace and Suttle, 1979; Pott et al., reversed by supplementation of copper, Mo as thiomolyb-
1999). Urinary elimination is concentration dependent, dates can have some direct toxic effects on copper depen-
resulting in relatively rapid elimination even with very dent enzymes. It is also possible that permanent tissue
large exposures. In lactating animals, Mo is excreted in damage, caused by severe copper depletion, may result in
the milk with content being dependent on the concentra- a nonresponse to copper supplementation in some clini-
tion being ingested (Archibald, 1951; Anke et al., 1985). cally affected animals. The exact mechanisms of some
Thus, exposure can be approximated by analysis of urine noncopper responsive toxic effects of Mo are poorly
or milk for Mo content across time and extrapolating defined or investigated, but it has been observed that high
back to the time of exposure (Lesperance et al., 1985). Mo concentrations can inhibit the in vivo activity of bio-
Just as sulfate can inhibit gastrointestinal absorption of logical enzymes, such as succinic acid oxidase, sulfide