Lack of stereoselectivity of the peroxisome proliferation induced by 2‐phenylpropionic acid: Evidence against a role for lipid disturbance in peroxisome proliferation

Abstract

The significance of disturbances of lipid metabolism caused by xenobiotic acyl-CoAs as possible causes of peroxisomal proliferation has been studied with the enantiomers of 2-phenylpropionic acid (2-PPA), the (R)-enantiomer of which is converted to the acyl-CoA in rats while its (S)-antipode is not. rac-2-PPA (250 mg/kg/day ip x 3) was shown to be an hepatic peroxisomal proliferator in male Sprague-Dawley rats on the basis of increases in microsomal cytochrome P-450 content and lauric acid hydroxylation and hepatic CN(-)-insensitive palmitoyl-CoA oxidation, a peroxisomal marker activity, while electron microscopy revealed a rise in the peroxisome/mitochondria ratio in hepatocytes. Further studies established the dose-response relationships for these biochemical changes. The (R)- and (S)-enantiomers were administered at a dose of 50 mg/kg/day ip x 3 and both were peroxisome proliferators of very similar potency. The effects of 100 mg/kg/day ip x 3 of the racemate, a dose giving ca. 75% of maximal response, were essentially additive of those of 50 mg/kg/day ip x 3 of its two component isomers. The stereoselectivity of acyl-CoA formation from the enantiomers of 2-PPA was confirmed by their differential inhibition of microsomal palmitoyl-CoA synthesis. Taken together, these data indicate that it is very unlikely that the acyl-CoA of 2-PPA plays any role in the peroxisomal proliferation which this compound causes in the rat.

Stereoselective effects of chiral clofibric acid analogs on rat peroxisome proliferator-activated receptor ? (rPPAR?) activation and peroxisomal fatty acid ?-oxidation

“…We and others have previously studied the effects of enantiomeric ligands in vivo on hepatic peroxisomal acyl CoA-oxidase, carnitine acetyl transferase (CAT), and microsomal CYPIVA1 activity. [16][17][18] Most in vivo studies report either a low or an absence of ligand stereoselectivity. In contrast, in vitro studies demonstrate that steric effects have a major influence on the stimulation of peroxisomal ACO and microsomal CYPIVA1 activities 18,19 and on the activation of PPAR.…”

Report on Carcinogens Monograph on Cumene

“…2-Phenylpropionic acid was one of the minor cumene metabolites identified in rat and mouse urine by Chen et al (2011) (see Table 2-1). Ahmad and Caldwell (1994) demonstrated that 2phenylpropionic acid is a peroxisome proliferator in rats. Peroxisome proliferation in rodents can lead to liver tumors and is characterized by hepatomegaly, proliferation of peroxisomes with associated enzyme changes, increased mitochondrial number and enzyme levels, proliferation of the smooth endoplasmic reticulum, enhanced synthesis of cytochrome P450 isoenzymes of the 4A family (Ahmad and Caldwell 1994).…”

“…Ahmad and Caldwell (1994) demonstrated that 2phenylpropionic acid is a peroxisome proliferator in rats. Peroxisome proliferation in rodents can lead to liver tumors and is characterized by hepatomegaly, proliferation of peroxisomes with associated enzyme changes, increased mitochondrial number and enzyme levels, proliferation of the smooth endoplasmic reticulum, enhanced synthesis of cytochrome P450 isoenzymes of the 4A family (Ahmad and Caldwell 1994). However, no histologic evidence of peroxisome proliferation was reported in the cumene NTP bioassay (NTP 2009).…”