Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate(DINP): a comparison of rat and human hepatocytes in vitro

Diethylhexylphthalate (DEHP) and diisononylphthalate (DINP) are plasticizer s with many important commercial, industrial and medical applications. Howe ver, both DEHP and DINP are rodent peroxisome proliferators (PPs), a class of compounds that cause rodent liver tumours associated with peroxisome pro liferation, induction of hepatic DNA synthesis and the suppression of apopt osis. Despite these effects in the rodent, humans appear to be nonresponsiv e to the adverse effects of PPs. Previously, we have shown that the fibrate hypolipidaemic peroxisome proliferator, nafenopin, induced DNA synthesis a nd suppressed apoptosis in rat but not in human hepatocytes. In this work, we have examined species differences in the response of rat and human hepat ocytes to DEHP and DINP in vitro. In rat hepatocytes in vitro, both DINP an d MEHP (a principle metabolite of DEHP and the proximal peroxisome prolifer ator) caused a concentration-dependent induction of DNA synthesis and suppr ession of both spontaneous and transforming growth factor beta 1 (TGF beta 1)-induced apoptosis. Similarly, both MEHP and DINP caused a concentration- dependent induction of peroxisomal beta-oxidation although the response to DINP was less robust. In contrast to the pleiotropic response noted in rat hepatocytes, neither DINP nor MEHP caused an induction of P-oxidation, stim ulation of DNA synthesis and suppression of apoptosis in human hepatocytes cultured from three separate donors. These data provide evidence for specie s differences in the hepatic response to the phthalates DEHP and DINP, conf irming that human hepatocytes appear to be refractory to the hepatocarcinog enic effects of PPs first noted in rodents.