Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Abstract

We have found here that there are clear structural requirements for peroxisome proliferation (monitored as increases in carnitine acetyltransferase activity, cyanide‐insensitive palmitoyl‐CoA oxidation, catalase and increases in the protein designated PPA 80) in mouse liver. From the investigation of ten structural analogues of 2‐ethylhexanoic acid, it could be concluded that the most effective proliferators all have an ethyl group as the substituent on carbon 2 of the main chain, which consists of six carbons. The further observation from this group of compounds that a charged group is required for effective proliferation leads us to speculate that such a group is involved in the molecular mechanism as well. Many, but not all, of the effective peroxisome proliferators in a second group of compounds contain a phenoxy group, often with a substituted α carbon. Interestingly, the 2,4‐dichlorophenoxyacetic and 2,4,5‐trichlorophenoxyacetic acids are both effective peroxisome proliferators, but the closely related p‐chlorophenoxyacetic acid is inactive in this respect, indicating that the chlorine atom at position 2 must be essential to the process in these cases. The results presented here also indicate that the structural requirements for proliferation of mitochondria are similar to those for proliferation of peroxisomes. Certainly, the most effective peroxisome proliferators also cause large increases in ‘mitochondrial’ protein and cytochrome oxidase activity, i.e. there is an obvious qualitative correlation.

Positive feedback between ethanolamine‐specific phospholipid base exchange and cytochrome P450 activities in rat liver microsomes. The effect of clofibric acid

“…It is worth noting that CLA added to the assay medium inhibited the ethanolamine‐specific PLBE reaction in a concentration‐dependent manner by 40% at a concentration range of 0.5–1 mM, probably due to the reduction of essential –SH groups in the enzyme. Another possibility is that the effect of starvation and CLA administration on increased synthesis of PE could be correlated to the elevated expression of cytochrome P450 isoenzymes [9–12]. In fact, in the course of our studies we have observed that enhancement of PE content in ER membranes from starved and CLA‐treated animals in comparison to rats fed ad libitum correlates well with the elevated expression of the cytochrome P450 CYP4A1 isoform, as detected using specific antibodies against rat CYP4A1 (Fig.…”

Peroxisome proliferation in response to xenobiotics

“…The ligand which binds to PPAR upon treatment of rodents with peroxisome proliferators is not yet known. One suggestion is that xenobiotic acyl-CoA derivatives bind to PPAR, since the vast majority of peroxisome proliferators contain a carboxylic moiety or another group which can be metabolized to such a moiety in uivo [6,7]. An alternative hypothesis is that peroxisome proliferators disturb cellular lipid metabolism such that an endogenous ligand for PPAR accumulates.…”

Biochemical Mechanisms of Induction of Hepatic Peroxisome Proliferation

“…The structural requirements for chemicals that cause hepatic peroxisome proliferation have been examined (100)(101)(102). The only unifying theme with regard to the diverse chemical structures which cause peroxisome prolifera tion is that they all contain an acid function or are readily metabolized to a 1.…”