Gene array analysis of the hepatic response to endotoxin in glutathione peroxidase-deficient mice

Glutathione peroxidase-1 (Gpx1) is a major defense enzyme against peroxides. Gpx1-deficient mice (Gpx1-/-) are more susceptible than wild-type (WT) mice to neutrophil-induced oxidant stress and liver injury produced by 700 mg/kg galactosamine and 10 microg/kg endotoxin (Gal/ET). However, it is unclear if Gal/ET modulates redox-sensitive genes in Gpx1-/- mice before the injury. Hepatic RNA was isolated 1.5 and 6 h after Gal/ET administration and subjected to gene expression analysis using Clontech customer-designed mouse toxicology array (600-gene). Gal/ET induced a significant increase in the expression of genes encoding inflammatory response, oxidative stress, growth arrest and responses to DNA damage and/or its repair. In general, more marked alterations were seen in Gpx1-/- as compared with WT mice, supporting the role of Gpx1 in cellular defense against oxidant stress to cope with aberrant gene expression. However, comparison with previous functional studies indicated that not all changes of gene expression are relevant for the pathophysiology. Thus, only a combination of gene array analysis with functional studies allows valid conclusions regarding mechanisms of cell injury.