LIPID METABOLITE INVOLVEMENT IN THE ACTIVATION OF THE HUMAN HEME OXYGENASE-1 GENE

Cellular effects of ultraviolet A (UVA) radiation include peroxidation of membrane lipids as well as a decrease in intracellular glutathione . We have investigated whether damage to membrane lipids is involved i n the activation of the human heme oxygenase-1 gene by UVA. Irradiatio n of human skin fibroblasts in the presence of the lipophilic antioxid ants, butylated hydroxytoluene and alpha-tocopherol, enhances the UVA- induced HO-1 mRNA accumulation, suggesting that peroxidation of plasma membrane lipids is not involved. Furthermore, sodium ascorbate, which induces lipid peroxidation mainly in the plasma membrane, induces HO- 1 mRNA to low levels only. The decrease in GSH by UVA radiation is not affected by the presence of the lipophilic antioxidants while ascorba te treatment increases the intracellular GSH by twofold above controls . These results indicate that peroxidation of internal membrane lipids , a decrease in the intracellular GSH levels and the integrity of the plasma membrane are all important for the UVA-induction of heme oxygen ase-1. Both nonenzymatic as well as enzymatic lipid peroxidation metab olites are inducers of heme oxygenasee-1. The nonenzymatic lipid perox idation product 4-hydroxynonenal induces heme oxygenase-l mRNA up to 4 0-fold and the phospholipase metabolites diacylglycerol and arachidoni c acid induce this mRNA by three- to sixfold above basal levels. We al so demonstrate that the cyclooxygenase metabolites of arachidonic acid are important for the UVA-activation of the heme oxygenase-1 gene.