Relation between induction of ornithine decarboxylase and specific gene expression in rat liver in response to the tumor promoter agent clofibrate.

The time course of changes in a number of biochemical parameters in rat liver was studied during 10 days of clofibrate administration. Ornithine decarboxylase (ODC) and putrescine levels began to increase within hours of the first dose and reached maxima at about 36 h (40 and 10 times control levels, respectively) and then returned to normal levels by 48 h. This ODC induction by clofibrate is different from that seen in compensatory liver hyperplasia or diethylnitrosamine administration in that it was not accompanied by elevations in cAMP or increased activation of cytoplasmic cAMP-dependent protein kinases, type I or II. Messenger RNA levels, notably of the species coding for the enzymes of the peroxisomal beta-oxidation pathway, increased in parallel with ODC and putrescine to reach a maximum also at 36 h. The enzymes of the peroxisomal beta-oxidation pathway, on the other hand, increased more gradually over time to reach a plateau at approximately 7 - 10 days. The magnitude of increase in mRNA (about 7-fold) was comparable to that of peroxisomal beta-oxidation as measured by cyanide-insensitive palmitoyl-CoA-dependent NAD+ reductase activity; comparable increases in the specific content of enoyl-CoA hydratase: beta-hydroxyacyl-CoA dehydrogenase and of peroxisomal thiolase were observed, as determined by SDS electrophoresis. A gradual increase in long-chain acyl-CoA (1.5-fold) followed the increase in beta-oxidation, whereas a 2-fold increase in acid-soluble CoA (free CoA and short-chain acyl-CoA) was seen as early as 36 h. This sequence of changes is at variance with proposals that increased levels of long-chain acyl-CoA mediate induction of peroxisomal beta-oxidation.