Induction of hepatic ornithine decarboxylase by hypolipidemic drugs with hepatic peroxisome proliferative activity

The present investigation was conducted to determine (1) ifhepatomegalic and mitogenic effects of selected hypolipidemicperoxisome proliferators are associated with an elevation ofhepatic ornithine decarboxylase (ODC) levels and (2) if inductionof ODC is a specific event associated with the development ofpreneoplastic hepatocellular foci and the eventual formationof hepatomas. Following a single i.p. dose of Wy-14, 643 (Wy),the hepatic ODC activity in rats rose sharply, reaching a peakat 8 h, and returned to the normal level by 24 h. Other peroxisomeproliferators tested (methyl clofenapate, BR-931 and nafenopin)also increased the hepatic ODC activities significantly 8 hafter i.p. administration of a single dose. Continuous dietaryadministration of Wy, whether or not these animals were previouslyinitiated with the carcinogen diethylnitros-amine (DEN), resultedin a sustained elevation of hepatic ODC activity. Although Wyexerted an enhancing effect on DEN-initiated tumorigenesis,there was no additional increase of ODC activity. There wasno correlation between the level of ODC induction and the presenceor absence of altered liver cell foci. These results suggestthat induction of ODC by peroxisome proliferators is not a specificevent associated with the development of preneoplastic fociand hepatocarcino-genesis, but is an event associated with thesustained maintenance of hepatomegaly and increased liver cellproliferation.