title: Reversibility and persistence of di-2-ethylhexyl phthalate (DEHP)- and phenobarbital-induced hepatocellular changes in rodents.
abstract: The tumor promotion stage of chemical carcinogenesis has been shown to exhibit a persistence of cellular effects during treatment and the reversibility of these changes upon cessation of treatment. Inhibition of gap-junctional intercellular communication and increased replicative DNA synthesis appear to be important in this process. The present study assessed the persistence and reversibility of gap-junctional intercellular communication inhibition, peroxisomal proliferation, and replicative DNA synthesis in livers from male F344 rats and B6C3F1 mice. Dietary administration of 20,000 mg/kg DEHP to male rats for 2 weeks decreased intercellular communication (67% of control) and enhanced replicative DNA synthesis (4.8-fold over control). Elevation of the relative liver weight and the induction of peroxisomal beta oxidation were also observed following treatment with 20,000 mg/Kg DEHP for 2 weeks. Following DEHP administration at a dose of 6000 mg/kg for 18 months, inhibition of gap-junctional intercellular communication persisted, and the relative liver weight and induction of peroxisomal beta oxidation remained elevated in both rats and male B6C3F1 mice. Treatment of rats and mice with phenobarbital for 18 months (500-mg/kg diet) also produced an increase in relative liver weight and a decrease in cell-to-cell communication. In recovery studies in which DEHP was administered to male F344 rats for 2 weeks and then withdrawn, the relative liver weight, rate of peroxisomal beta oxidation, increase in replicative DNA synthesis, and inhibition of gap-junctional intercellular communication returned to control values within 2 to 4 weeks after DEHP treatment ceased. Recovery studies with phenobarbital produced similar results. The primary active metabolite of DEHP, mono-2-ethylhexyl phthalate (MEHP), was detected in the livers of animals treated with DEHP for greater than 2 weeks. However, it could not be detected after removal of DEHP from the diet for 2 weeks. This study demonstrated that inhibition of gap-junctional intercellular communication, along with indicators of peroxisomal proliferation, including increased relative liver weight and enhanced peroxisomal beta oxidation, persist while DEHP treatment continues but reverses when treatment is stopped. Studies with phenobarbital produced a similar pattern of response.
authors.affiliation: Division of Toxicology, Department of Pharmacology and Toxicology, Indiana University School of Medicine, 635 Barnhill Drive, MS-1021, Indianapolis, IN 46202, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: L M
authors.initials: LM
authors.lastname: Kamendulis
authors.forename: D C
authors.initials: DC
authors.lastname: Ackley
authors.forename: J H
authors.initials: JH
authors.lastname: Smith
authors.forename: G
authors.initials: G
authors.lastname: Pugh
authors.forename: A W
authors.initials: AW
authors.lastname: Lington
authors.forename: R H
authors.initials: RH
authors.lastname: McKee
authors.forename: J E
authors.initials: JE
authors.lastname: Klaunig
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D004261:DNA Replication / Q000187:drug effects; D004032:Diet; D004051:Diethylhexyl Phthalate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D010795:Phthalic Acids / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D005227:Fatty Acids; D010795:Phthalic Acids; C032279:phthalic acid; D004051:Diethylhexyl Phthalate; C016599:mono-(2-ethylhexyl)phthalate; D010634:Phenobarbital