The
nitric oxide (NO) donor, O2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (
V-PYRRO/NO), is metabolized by
P450 enzymes to release NO within the liver and is effective in protecting against hepatotoxicity of
endotoxin and
acetaminophen. This study examined the effects of
V-PYRRO/NO on
cadmium (Cd) hepatotoxicity in mice. Mice were given multiple
injections of
V-PYRRO/NO (10 mg/kg, s.c. at 2-h intervals) before and after a hepatotoxic dose of Cd (3.7 mg/kg Cd as
CdCl2, i.p.).
V-PYRRO/NO administration reduced Cd-induced hepatotoxicity as evidenced by reduced serum
alanine aminotransferase activity, improved pathology, and reduced hepatic lipid peroxidation. The protection by
V-PYRRO/NO was not mediated by altered Cd distribution to the liver or within hepatic subcellular fractions. Similar inductions of
metallothionein, a metal-
binding protein, were observed in mice receiving Cd alone or Cd plus
V-PYRRO/NO. Real-time reverse transcription-polymerase chain reaction analysis revealed that
V-PYRRO/NO administration suppressed the expression of
inflammation-related genes such as macrophage inflammatory protein-2,
CXC chemokine, thrombospondin-1, intracellular adhesion molecular-1, and
interleukin-6.
V-PYRRO/NO also suppressed the expression of
acute phase protein genes and genes related to cell-death pathways, such as c-jun/AP-1,
nuclear factor-kappaB, early response growth factor-1,
heme oxygenase-1,
caspase-3, growth arrest, and
DNA-damaging protein-153. In summary, the liver-selective NO donor,
V-PYRRO/NO, protects against Cd hepatotoxicity in mice. This protection is not mediated through altered distribution of Cd but may be related to reduced hepatic
inflammation, reduced
acute phase responses, and the suppression of cell-death-related components.