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

MERCURY 211
2. HEALTH EFFECTS
Mercury has been shown to affect hepatic microsomal enzyme activity (Alexidis et al. 1994). Intraperitoneal
administration of mercuric acetate (6.2 µmol/kg/day) once daily for 6 days or once as a single
dose of 15.68 µmol/kg resulted in an increase in kidney weight and a significant decrease in total
cytochrome P-450 content. The single 15.68 µmol/kg injection resulted in the reduction of both
microsomal protein level and P-450 content, possibly resulting from the generation of free radicals during
the Hg ++ intoxication process.
Through alterations in intracellular thiol status, mercury can promote oxidative stress, lipid peroxidation,
mitochondrial dysfunction, and changes in heme metabolism (Zalups and Lash 1994). HgCl2 has been
shown to cause depolarization of the mitochondrial inner membrane, with a consequent increase in the
formation of H2O2 (Lund et al. 1993). These events are coupled with a Hg ++ -mediated glutathione depletion
and pyridine nucleotide oxidation, creating an oxidant stress condition characterized by increased
susceptibility of the mitochondrial membrane to iron-dependent lipid peroxidation. Lund et al. (1993)
further postulated that mercury-induced alterations in mitochondrial calcium homeostasis may exacerbate
Hg ++ -induced oxidative stress in kidney cells. As a result of oxidative damage to the kidneys, numerous
biochemical changes may occur, including the excretion of excess porphyrins in the urine (porphyrinuria).
In a study of the mechanism of porphyrinogen oxidation by mercuric chloride, Miller and Woods (1993)
found that mercury-thiol complexes possess redox activity, which promotes the oxidation of porphyrinogen
and possibly other biomolecules.
The steps between thiol binding and cellular dysfunction or damage have not been completely elucidated,
but several theories exist. Conner and Fowler (1993) have suggested that following entry of the mercuric
or methylmercuric ion into the proximal tubular epithelial cell by transport across either the brush-border
or basolateral membrane, mercury interacts with thiol-containing compounds, principally glutathione and
metallothionein. This interaction initially produces alterations in membrane permeability to calcium ions
and inhibition of mitochondrial function. Through unknown signaling mechanisms, mercury subsequently
induces the synthesis of glutathione, various glutathione-dependent enzymes, metallothionein, and several
stress proteins (Conner and Fowler 1993). In the kidneys, epithelial cell damage is believed to occur as the
result of enhanced free radical formation and lipid peroxidation (Gstraunthaler et al. 1983). Treatment
with mercury results in depletion of cellular defense mechanisms against oxidative damage such as
glutathione, superoxide dismutase, catalase, and glutathione peroxidase (Gstraunthaler et al. 1983).
Further, enhancement of glutathione peroxidase has been observed in mercury-treated rats in direct
relationship with kidney mercury content (Guillermina and Elias 1995), but inhibition of renal redox cycle