Phthalates enzyme induction

A considerable amount of information on the hepatic effects of orally administered di(2-ethylhexyl) phthalate indicates that it causes hepatic peroxisome proliferation (ultrastructural effects and enzyme induction), hepatomegaly and increased replicative DNA synthesis in rats and mice. At a lower magnitude in Syrian hamsters, enzyme induction and hepatomegaly have been observed (ultrastructural effects and replicative DNA synthesis have not been evaluated). Guinea-pigs, marmosets and cynomolgus monkeys evaluated under the same or similar experimental conditions did not exhibit peroxisome proliferation responses. Studies of di(2-ethylhexyl) phthalate... 

Hexachlorobenzene acted like a weak Ah receptor agonist and caused an up to 40% decrease in specific hepatic cytosol binding of 2,3,7,8-TCDD in rat cells (Hahn et al. 1989b). Similarly, 2,3,7,8-TCDD-induced myelotoxicity and enzyme induction was antagonized by 1-amino-3,7,8-trichlorodibenzo-p-dioxin in B6C3Fj mice presumably by competitive binding to the cytosolic Ah receptor (Luster et al. 1986). Comparable effects were observed in vitro in murine bone-marrow-cells cultures. Treatment of Fischer 344 rats orally with di(2-ethylhexyl)phthalate (DEHP) before or after oral administration of... 

Studies of PPARa activation in vitro have shown that di(2-ethylhexyl) phthalate metabolites are capable of activating PPARa. A study of PPARa knock-out mice treated with di(2-ethylhexyl) phthalate in vivo demonstrated that the increased liver weights and induction of peroxisomal and microsomal enzymes are absolutely dependent on PPARa (Ward et al, 1998). 

Induction of peroxisome proliferation following treatment with DEHP is not due to the parent compound, but to DEHP metabolites. Studies with MEHP in vitro have demonstrated that the proximate peroxisome proliferators are mono(2-ethyl-5-oxohexyl) phthalate (metabolite VI) and mono(2-ethyl-5-hydroxyhexyl) phthalate, (metabolite IX) and that for 2-ethylhexanol, the proximate proliferator is 2-ethylhexanoic acid (Elcombe and Mitchell 1986 Mitchell et al. 1985a). Similar findings were observed by Maloney and Waxman (1999), who showed that MEHP (but not DEHP) activated mouse and human PPARa and PPARy, while 2-ethylhexanoic acid activated mouse and human PPARa only, and at much higher concentrations. Based on its potency to induce enzyme activities, such as the peroxisomal fatty acid (3-oxidation cycle and carnitine acetyltransferase, DEHP might be considered a relatively weak proliferator. 

B. G. Lake, T. J. B. Gray, D. F. V. Lewis, J. A. Beamand, K. D. Hodder, R. Purchase, and S. D. Gangolli, Toxicol. Ind. Health, 3, 165 (1987). Structure-Activity Relationships for Induction of Peroxisomal Enzyme Activities by Phthalate Monoesters in Primary Rat Hepatocyte Cultures. 

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