Page 1147 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Ionophores Chapter | 78 1079

VetBooks.ir TOXICITY Monensin
Pathogenesis

The exact mechanism of the toxicity induced by iono- Free Sarcolemmal Membrane
phores is not known. However, reasonable hypotheses radicals membrane perturbation
have been generated based on their inherent ionophoric
activity (Van Vleet et al., 1983c, 1991; Novilla and
Folkerts, 1986). All ionophores facilitate transmembrane Influx of
Oxidation Lipid
ion fluxes and dissipation of ion gradients, which are Na +
products + peroxidation
exaggerated at toxic levels. Cells respond to the metabolic Efflux of K
insult by expending energy to maintain homeostasis. pH Changes
When homeostatic mechanisms are exceeded, toxicity
1 11
ensues from excessive influxes of Na and Ca leading Catecholamine Increased net Insufficient Ca ++
to degeneration and necrosis of cardiac and skeletal mus- release influx of Ca ++ pumped out of cell
cle cells. Although the ionophore mode of action is sim-
ple, four biochemical changes, including intracellular pH
effects, calcium overloading, catecholamine release and ++
Excess uptake of Ca
lipid peroxidation, probably occur during ionophore toxi- by mitochondria
cosis (Fig. 78.4).
In the diagram, monensin facilitates cation exchange
diffusion as it intercalates with plasma membranes Mitochondrial
(Pressman, 1976; Reed, 1982). The exaggerated pharma- damage
cologic activity at toxic levels disrupts not only osmotic
gradients but the intracellular pH as well. Since drastic
changes in acid base balance are incompatible with life,
Lack of energy
the pH shifts may be responsible for the peracute deaths
observed with very high toxic levels of ionophores
(Novilla and Folkerts, 1986). The monensin-induced entry
1 Elevated cytoplasmic Ca ++
of Na is followed by entry of calcium, due to an
levels
ATPase-driven exchange mechanism at the cell mem-
brane. A calcium ionophore like lasalocid or A23817 pro-
11
motes Ca entry directly. Ionophores are known to
11 Muscle necrosis
trigger the release of Ca from intracellular stores fur-
11
ther increasing Ca levels in the cytoplasm. FIGURE 78.4 Probable sequence of events induced by monensin in
Two other mechanisms contribute to calcium over- muscle cells. Adapted from Novilla, M.N., Folkerts, T.M., 1986.
loading: exaggerated release of neurotransmitters like Ionophores: monensin, lasalocid, salinomycin, narasin. In: Howard, J.L.
catecholamines and increased peroxidation of lipids. (Ed.), Current Veterinary Therapy-Food Animal Practice. Academic
Press, New York, NY, pp. 359 363.
Monensin, lasalocid, and salinomycin have been reported,
respectively, to release catecholamines from adrenal chro-
membrane, mitochondria and sarcoplasmic reticulum.
maffin cells, transport catecholamines directly, or aug-
However, toxicity overwhelms this buffering mechanism
ment catecholamine plasma levels. The degradation
and a vicious cycle ensues, resulting in calcium overload-
products of catecholamines have been implicated in myo-
ing. Elevated calcium levels then activate muscle proteases
cardial necrosis, through the formation of free radicals
and phospholipases which initiate degradative processes
and calcium influx (Reichenback and Benditt, 1982).
(disassembly of myofilaments and membrane damage) in
Since ionophores are lipophilic and have detergent prop-
striated muscle and ultimately cell death (Van Vleet et al.,
erties, dose-related perturbations of plasma membranes
1983c, 1991; Sandercock and Mitchell, 2004).
can promote increased lipid peroxidation. It is known that
lipid peroxidation promotes membrane damage, and con-
11
sequently increases Ca influx. Occurrence
Since they are not mutually exclusive, one or more of
the above pathogenic mechanisms may increase calcium Generally, the marketed ionophore products have been
concentrations in the cell. The rise in intracellular calcium found to be safe and effective in the target species pro-
can be buffered by calcium pumps in the plasma vided the approved dosage ranges. However, excessive