revised final - Agency for Toxic Substances and Disease Registry ...

MERCURY 212
2. HEALTH EFFECTS
enzymes in vivo did not appear to be a significant determinant of the increased lipid peroxidation observed
during HgCl 2-induced nephrotoxicity. The selenium-dependent form of glutathione peroxidase is highly
sensitive to inhibition by mercury, and it has been proposed that mercury interactions with selenium in the
epithelial cells limit the amount of selenium available for this enzyme (Nielsen et al. 1991). Depletion of
mitochondrial glutathione and increases in mitochondrial hydrogen peroxide at the inner mitochondrial
membrane (Lund et al. 1991) may contribute to acceleration of the turnover of potassium and magnesium
observed at this membrane (Humes and Weinberg 1983). Acute renal failure resulting from mercury
exposure has been proposed to result from decreased renal reabsorption of sodium and chloride in the
proximal tubules and increased concentrations of these ions at the macula densa (Barnes et al. 1980). This
increase in ions at the macula densa, in turn, results in the local release of renin, vasoconstriction of the
afferent arteriole, and filtration failure. These authors based this hypothesis on the observation that saline
pretreatment of rats prior to mercuric chloride treatment did not prevent the proximal tubular damage but
did prevent the acute renal failure. The saline pretreatment was suggested to have depleted the glomerular
renin and thereby prevented the cascade of events occurring after accumulation of sodium and chloride ions
at the glomerular macula densa (Barnes et al. 1980). A pivotal role for extracellular glutathione and
membrane-bound γ-glutamyltransferase has also been identified in the renal incorporation, toxicity, and
excretion of inorganic mercury (HgCl2) in rats (Ceaurriz et al. 1994).
A similar mechanism for the promotion of neuronal degeneration by mercury has been proposed (Sarafian
and Verity 1991). Increases in the formation of reactive oxygen species in several brain areas have been
observed following intraperitoneal administration of methylmercuric chloride to rodents (Ali et al. 1992;
LeBel et al. 1990, 1992). A dissociation between increases in lipid peroxidation and cytotoxicity has been
demonstrated by showing inhibition of the lipid peroxidation with α-tocopherol without blocking the
cytotoxicity (Verity and Sarafian 1991). These authors were able to show partial protection against the
cytotoxicity with ethylene glycol tetra-acetate (EGTA), suggesting that increases in intracellular calcium
may play a role in the cytotoxicity. They ultimately concluded that a synergistic interaction occurred
between changes in intracellular calcium homeostasis and intracellular thiol status, culminating in
lipoperoxidation, activation of Ca2+-dependent proteolysis, endonuclease activation, and phospholipid
hydrolysis (Verity and Sarafian 1991). It has been suggested that neurons are highly sensitive to mercury
either because of their low endogenous glutathione content or their inefficient glutathione redox activity.
Inhibition of protein synthesis has been reported in neurons from rats exposed to methylmercury (Syversen
1977). However, it is unknown whether this inhibition is secondary to neuronal cytotoxicity.