Studies on the hepatic effects of orally administered di-(2-ethylhexyl) phthalate in the rat

Abstract

A sequential study of hepatic effects was conducted in young male Wistar albino rats following daily oral intubation of di-(2-ethylhexyl) phthalate (DEHP) at a dose of 2000 mg/kg for 21 days. The relative liver weights of the animals increased progressively with the duration of the treatment. Alcohol dehydrogenase activity and microsomal protein and cytochrome P-450 contents showed a marked initial increase followed by a reversal as the treatment progressed. In contrast to this biphasic response, the activities of microsomal glucose-6-phosphatase, aniline 4-hydroxylase, and mitochondrial succinate dehydrogenase activity were significantly depressed, as observed both biochemically and histochemically, throughout the period of exposure. Parallel electronmicroscopic studies revealed a progressive dilatation of the smooth and rough endoplasmic reticulum, mitochondrial swelling and an increase in microbodies. Investigations carried out on the metabolic fate of [ 14C]DEHP in animals prior to and during the course of DEHP treatment showed no significant differences in the excretion pattern of radioactivity. Furthermore, there was no evidence indicating the storage of phthalate residues in the liver. Studies on the comparative effects of phthalic acid, 2-ethylhexanol, and mono-(2-ethylhexyl)phthalate (MEHP) orally administered at dose levels equimolar to DEHP for 7 days showed that the biochemical and ultrastructural changes in the hepatic endoplasmic reticulum and mitochondria in DEHP pretreatment were substantially reproducible by the administration of MEHP. Additionally, it was found that 2-ethylhexanol treatment led to an increase in the number of microbodies. The results indicate that the partial hydrolysis of DEHP to the monoester (MEHP) is the degradative step which determines the hepatic changes produced by DEHP.