SELENIUM METABOLISM IN ISOLATED HEPATOCYTES - INHIBITION OF INCORPORATION IN PROTEINS BY MONO(2-ETHYLHEXYL)PHTHALATE, A METABOLITE OF THE PEROXISOME PROLIFERATOR DI(2-ETHYLHEXYL)PHTHALATE

Di(2-ethylhexyl)phthalate (DEHP), a rat liver carcinogen, induces peroxisomal proliferation and a concomitant oxidative stress, but decreases liver glutathione peroxidase (GSH-Px) activity. This enzyme is a selenoprotein and we have investigated the influence of mono(2-ethylhexyl)pthalate (MEHP), a major metabolite of DEHP, on selenium incorporation in hepatocellular proteins. [Se-75]Selenious acid (6 nM) was added to primary cultures of rat hepatocytes and protein incorporation was assessed by SDS-PAGE and autoradiography. High concentrations of MEHP (1.0-3.0 mM) inhibited selenium labeling of all major selenoproteins in 3-24 h experiments, but also inhibited protein synthesis as assessed by leucine incorporation. The protein synthesis inhibition was reversible. Lower concentrations of MEHP (0.3-0.5 nM) did not decrease the Se-75-labeling in 24 h experiments and did not inhibit leucine incorporation. However, conditions that significantly induced peroxisomal proliferation also affected the Se-75-labeling. Thus in 72 h experiments, 0.05-0.25 mM MEHP increased the labeling of a 58 kd protein, decreased the labeling of a 23 kd protein with the same mol. wt as GSH-Px), had no effect on a 20 kd protein and decreased the labeling of a 15 kd protein (as compared to MEHP-free control plates). The pattern of changes associated with peroxisomal proliferation mimicked that seen in livers from selenium-deficient animals, as reported by others. These data indicate that the bioavailability of selenium is decreased by DEHP. This effect may relate to a transient inhibition of protein synthesis, but also to the DEHP-induced peroxisomal proliferation.