title: Structure-activity relationships for induction of peroxisomal enzyme activities by phthalate monoesters in primary rat hepatocyte cultures.
abstract: Rat hepatocytes were cultured for 70 hours with a series of four isomeric octyl and five isomeric hexyl phthalate monoesters, and their effects on peroxisomal fatty acid beta-oxidation (palmitoyl-CoA oxidation) and carnitine acetyltransferase activities determined. All nine monoesters produced dose-related increases in enzyme activities and marked quantitative compound potency differences were observed. Generally octyl isomers were more potent than hexyl isomers and 2- and 3-ethyl substituted isomers were more potent than their straight chain and 1-ethyl substituted analogs. For example, mono(2-ethylhexyl)phthalate was more potent than mono(1-ethylhexyl)phthalate, and this was also observed after oral administration of the two isomers to rats for seven days. The cell culture data for induction of palmitoyl-CoA oxidation were used to generate quantitative structure-activity relationships. Relatively poor correlations were observed between biological activity and simple hydrophobic parameters, but a good correlation was obtained when compound electronic structural parameters, obtained by molecular orbital calculations, were employed. These studies demonstrate relationships between biological activity and chemical structure for a series of phthalate monoesters and indicate the potential usefulness of primary rat hepatocyte cultures to screen compounds for peroxisome proliferation.
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects*; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000201:enzymology; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010795:Phthalic Acids / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
chemical_list: D010795:Phthalic Acids; D010171:Palmitoyl Coenzyme A