Abstract
The present work has investigated the species differences and mechanisms involved in hepatic peroxisome proliferation. The suitability of primary hepatocyte cultures as an in vitro model for this phenomenon was determined. The effects of a range of peroxisome proliferators on cultured rat hepatocytes were both qualitatively and quantitatively similar to the effects observed in the liver of the rat in vivo. A species difference in the hepatic response to orally administered di-(2-ethyl hexyl)phthalate (DEHP) was demonstrated in the rat and the marmoset. This species difference phenomenon was further investigated using primary guinea pig and marmoset hepatocyte cultures. Peroxisome proliferation as seen in rat hepatocytes was not observed in guinea pig or marmoset hepatocytes with any agent tested. Similarly, peroxisome proliferation was not observed in cultured human hepatocytes. These observations are suggested to infer an inherent difference in sensitivity of the guinea pig, marmoset and human hepatocyte to peroxisome proliferation. The mechanism by which DEHP elicits peroxisome proliferation in the rat liver has been investigated. The metabolites of DEHP produced by o-1-oxidation of the monoester (metabolite IX [mono-(2-ethyl-5-hydroxy hexyl phthalate] and metabolite VI [mono-(2-ethyl-5 oxo hexyl phthalate]) were shown to be potent peroxisome proliferators in cultured rat hepatocytes. These metabolites produced a transient increase in intracellular neutral lipid in cultured rat hepatocytes. Metabolite Vis was further shown to interfere with hepatic lipid metabolism, causing an inhibition of mitochondrial medium chain acyl carnitine oxidation specifically. Hence it is proposed that the species difference in peroxisome proliferation is due to differences in response of guinea pig, marmoset and human hepatocytes to the accumulation of intracellular lipid.