© 1990 Oxford University Press
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Di(2-ethylhexyl)phthalate alters carbohydrate enzyme activites and foci incidence in rat liver
Institute of Veterinary Biochemustry, University of Geissen Berlin, FRG
2Institute of Toxicology, GSF Neuherberg Berlin, FRG
3Umweltbundesamt Berlin, FRG
The effect of di(2-ethylhexyl)phthalate (DEHP) on diethyl nitrosainlne (DEN)-initiated preneoplastic liver lesions with expression of gamma-glutamyltranspeptidase (GGTase) and loss of adenosine trlphosphatase (ATPase) as well as alterations of hepatic carbohydrate metabolism in male and female Sprague-Dawley rats have been investigated. Two treatment schedules have been compared with respect to their sensitivity by the histochemical demonstration of preneoplastic islands and by the biochemical determination of alterations in enzyme activities of liver homogenates and of serum, the last indicating hepatotoxicity. For initiation, a single dose of DEN was given, followed by treatment with various doses of DEHP given three times weekly by gavage for 7 or 11 consecutive weeks. As histochemical enzyme markers, the expression of positive GGTase as well as the deficiency in ATPase were used for identification of liver foci. The weanling female rats (protocol A) were found to be more sensitive to the carcinogenic effect of DEN in view of foci incidence than the mature male rats which underwent partial hepatectomy prior to DEN application. The administration of 200 mg DEHP/kg body increased the incidence of ATPase-deficient foci in both male and female rats; however, concentrations of 1000 and 2000 mg DEHP/kg decreased the incidence of liver foci. The number of foci with expression of GGTase was only slightly increased in female rats following a DELIP concentration of 50 mg/kg, and 200 mg/kg body wt. DEHP alone did not induce preneoplastic lesions that could be identified by these two markers. Biochemical investigations indicate that DEHP alters the metabolic pattern in liver. An increase of the NADP-linked enzymes glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, extra-mitochondrial ICDH as well as an enhancement of NAD-dependent 
-G3PDH and lactate dehydrogenase were found following DEHP administration. On the other hand the glycolytlc enzymes pyruvate kinase (PK) and enolase as well as the gluconeogenelic enzyme fructose-1,6.-bisphosphatase (FBPase) were significantly reduced. In protocol B (male rats) the reactions of PK, FBPase and malic enzyme were more altered after DEHP exposure than in protocol A, while the activity of G6PDH was more increased in protocol A. Most enzymes being involved in the carbohydrate metabolism are influenced by DEHP In a dose-dependent manner. There was no increase in senim FBPase activity in both male and female rats after DEHP treatment but a reduction of glutamate-oxalate-transaminase and glutainate-pyruvate-transaminase activities was observed. This and the fact that the control and DEHP-treated animals had similar weight gains indicate that DEHP does not exert a significant hepatotoxicity effect.
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