PM04 Phthalate Esters: Fate and Effects
Exhibit Hall
8:00 AM - Monday
(PM022) Unequivocal estrogenic activity of phthalate esters featured with ring hydroxylation through metabolism.
Okamoto, Yoshinori1, Okajima, Kana1, Toda, Chitose1, Ueda, Koji1, Hashizume, Kiyomatsu1, Itoh, Kazuo1, Kojima, Nakao1, 1 Faculty of Pharmacy, Meijo University, Nagoya, Japan
ABSTRACT- Many researchers have found evidence of the estrogenic effects of phthalate esters (PEs), but the disruption mechanism is not fully elucidated. Once PEs are hydroxylated at the ring 4-position, the resulting compounds exhibit unequivocal binding affinity for human estrogen receptors. In this study, we first succeeded to demonstrate the generation of the potent estrogenic metabolite from PEs. Dimethyl phthalate (DMP) were used as a representative for the metabolism of PEs via rat liver microsomes. Among the metabolites detected by HPLC, one was consistent with an authentic compound, 4-hydroxylated DMP (DMP-4OH) on their HPLC profiles. Together with the UV and MS data, the metabolite was concluded to be DMP-4OH. The formation of DMP-4OH was NADPH-dependent and inhibited by proadifen hydrochloride (SKF-525A), demonstrating the involvement of cytochrome P450s (CYPs). Using specific inhibitors of each CYP isoform, CYP 2A, 2E and 3A were shown to catalyze the 4-hydroxylation of DMP. We propose that this ring-hydroxylated metabolite could be a key active species in the endocrine disrupting processes of PEs. Our previous researches revealed that PEs acquired estrogenic activities through ring hydroxylation by light exposure. Therefore, it is important that the risk of environmental chemicals is assessed comprehensively including their metabolites and photoproducts.
Key words: estrogenic activity, phthalate esters, metabolic activation, ring hydroxylation