PPAR alpha- and DEHP-Induced Cancers

Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and a potentially nongenotoxic carcinogen. Its mechanism had been earlier proposed based on peroxisome proliferator-activated receptor alpha (PPAR alpha) because metabolites of DEHP are agonists. However, recent evidence also suggests the involvement of non-PPAR alpha multiple pathway in DEHP-induced carcinogenesis. Since there are differences in the function and constitutive expression of PPAR alpha among rodents and humans, species differences are also thought to exist in the carcinogenesis. However, species differences were also seen in the lipase activity involved in the first step of the DEHP metabolism, which should be considered in DEHP-induced carcinogenesis. Taken together, it is very difficult to extrapolate the results from rodents to humans in the case of DEHP carcinogenicity. However, PPAR alpha-null mice or mice with human PPAR alpha gene have been developed, which may lend support to make such a difficult extrapolation. Overall, further mechanical study on DEHP-induced carcinogenicity is warranted using these mice. Copyright (C) 2008 Y. Ito and T. Nakajima.