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)phthalate (MEHP), a major metabolite of DEHP, on selenium incorporation in hepatocellular proteins. [75Se]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 mM) did not decrease the 75Se-labeling in 24 h experiments and did not inhibit leucine incorporation. However, conditions that significantly induced peroxisomal proliferation also affected the 75Se-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.
Garberg
P
P
National Institute of Occupational Health, Solna, Sweden.
Högberg
J
J
D000818:Animals; D002478:Cells, Cultured; D004051:Diethylhexyl Phthalate / Q000378:metabolism* / Q000633:toxicity* / Q000031:analogs & derivatives; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008830:Microbodies / Q000187:drug effects; D014176:Protein Biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D012643:Selenium / Q000378:metabolism*
D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate; D012643:Selenium