Abstract
The mechanism of induction of peroxisome proliferation by xenobiotics was investigated. Firstly, the evidence for a soluble cytosolic receptor was evaluated. No specific displaceable binding of [[3]H]-nafenopin or [[3]H]-ciprofibrate to rat liver subcellular fractions was observed. It was concluded that there is no evidence for a cytosolic receptor for the xenobiotic peroxisome proliferators. The time course of induction of several parameters were determined at the molecular, protein and enzyme activity levels, following a single i. p. dose of sodium clofibrate. Cytochrome P-450 IVA1 and lauric acid hydroxylase activity showed a biphasic response to sodium clofibrate, with the major peak occurring between 18 and 24 hours post dose. The minor peak occurred after 30 minutes post dose and the activities returned to basal level after 2 hours. Peroxisomal beta-oxidation, and the levels of bifunctional protein, responded in a monophasic manner, peaking approximately 24 hours post dose. Cytochrome P-450 IVA1 and lauric acid hydroxylase were therefore induced before peroxisomal beta-oxidation and bifunctional protein. The effect of cycloheximide on the induction of peroxisome proliferation by clofibrate was investigated. The prior administration of cycloheximide ablated the induction of cytochrome P-450 IVA1 protein, lauric acid hydroxylase, peroxisomal beta-oxidation and acyl-CoA mRNA, although the induction of cytochrome P-450 IV A1 mRNA was not affected. The administration of clofibrate prior to cycloheximide was toxic, resulting in the death of 5 out of 6 rats. The data, taken collectively, is not inconsistent with a cascade type mechanism of induction which postulates that the induction of peroxisomal beta-oxidation is dependent upon the prior induction of cytochrome P-450 IVA1.