Oxidative Stress–Mediated Down–Regulation of Rat Hydroxyacid Oxidase 1, A Liver–Specific Peroxisomal Enzyme

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Abstract
Hydroxyacid oxidase 1 (Hao1) is a liver–specific peroxisomal enzyme that oxidizes glycolate to glyoxylate with concomitant production of H2O2. In Hao1 messenger RNA (mRNA), an iron–responsive element (IRE) homologous to the sequence recognized by iron regulatory proteins (IRP), key regulators of iron homeostasis, is present, but the involvement of iron in Hao1 regulation remains unclear. In this study, we found a reduction of Hao1 mRNA content in livers of rats with chronic dietary iron overload, which showed decreased IRP activity and higher ferritin expression as expected, but also induction of heme oxygenase (HO–1), a marker of oxidative damage, and lipid peroxidation. Hao1 mRNA levels were not altered significantly in livers of rats administered doses of iron sufficient to induce ferritin expression and to repress IRP activity, but not to activate HO–1 and to promote lipid peroxidation, as well as in the liver of iron–deficient rats. These observations were not consistent with a post–transcriptional down–regulation of Hao1 by iron through the IRE/IRP pathway and suggested an effect of reactive oxygen species (ROS). Indeed, a marked decrease of Hao1 mRNA was observed in the liver of rats subjected to oxidative stress induced by either glutathione depletion or postischemic reperfusion. Nuclear run–on analysis showed an effect of ROS at the transcriptional level. In conclusion, down–regulation of Hao1 expression during oxidative stress may provide a mechanism to prevent excessive H2O2 formation in liver peroxisomes and may represent the prototype of a poorly recognized but potentially relevant response to oxidative injury involving down–regulation of ROS–producing enzymes.

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