Polydispersity of rat liver peroxisomes induced by the hypolipidemic and carcinogenic agent clofibrate

1. The present study has confirmed that the hypolipidemic and carcinogenic agent clofibrate induces a marked increase in the specific activity of some peroxisomal marker enzymes in rat liver homogenates, notably of the palmitoyl-CoA dependent dehydrogenase and catalase activities. 2. Clofibrate was found to induce a marked polydispersity of the peroxisomes as determined by analytical differential centrifugation of homogenates and morphometric analysis of hepatocytes. 3. Two major populations of peroxisomes were detected by analytical differential centrifugation under conditions which reduce the hydrostatic pressure effects on the organelle to a minimum. Using urate oxidase as the marker enzyme, the S4,B-values of the two populations were estimated to 1 1 860 S and 4240 S, both different from that of the homogenous population of peroxisomes in the control animals (S4,B approximately equal to 6680 S). The 4240 S-population induced by clofibrate revealed a high specific activity relative to that of of urate oxidase and particularly relative to that of catalase, which was very low. In addition, a less distinct population of particles (870 S lees than S lees than 4240 S) contained more than 50% of the total particle-bound palmitoyl-CoA dependent dehydrogenase activity sedimented at a centrifugal effect of t integral of 0 rmp(2)dt = 1.5 x 10(10) min(-1), but not urate oxidase and catalase activities. This fraction was not observed in the homogenates of normal rats. As in the normal controls, the palmitoyl-CoA dependent dehydrogenase activity was found to be particle-bound (S greater than 870 S). 4. Morphometric analyses of randomly selected hepatocytes revealed that after clofibrate treatment the relative volume fraction of the peroxisomes increased by a factor of 5.5 and thier average diameter and volume by a factor of 1.3 and 2.1, respectively. Furthermore, the frequency of electron-dense matrix cores decreased on clofibrate treatment. In contrast, no change was observed in the average size of the mitochondria, and their relative volume fraction increased only by a factor of 1.2. 5. The clofibrate induced changes in eh morphological and biochemical properties of rat liver peroxisomes appears to be a very useful model system in which to study the biogenesis as well as the biochemical and physiological role(s) of this organelle in mammalian cells.