Effects of phthalate ester derivatives including oxidized metabolites on coactivator recruiting by PPARalpha and PPARgamma.
Phthalate esters (PEs), a group of environmental chemicals, affect biological systems via endocrine and lipid metabolism modulations. These effects are believed to be mediated in part by peroxisome proliferator-activated receptors (PPARs). Evaluations of PE activities as ligands toward PPARs have been investigated in many studies on their primary metabolites, monoesters. However, the activities of various other metabolites, including oxidized derivatives, remain to be determined. Here, we have evaluated the PPAR ligand activities of these PE derivatives by in vitro coactivator recruiting assay. Mono(2-ethyl-5-hydroxyhexyl)phthalate, the most abundant metabolite of di-(2-ethylhexyl)phthalate (DEHP), was less active than mono(2-ethylhexyl)phthalate (MEHP) as a PPAR ligand. Other derivatives oxidized at the alkyl group and benzene ring of DEHP, MEHP, dibutyl phthalate and its monoester were also investigated and some affected PPAR activities. Unexpectedly, MEHP as well as its further oxidized metabolite did not show clear activity for PPARalpha, although MEHP is believed to interact with PPARalpha. This might imply indirect PPAR-mediated mechanisms that lead to observed biological effects such as peroxisome proliferation.
Kusu
Rena
R
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya, Japan.
Oishi
Ami
A
Kakizawa
Kimi
K
Kimura
Tomomi
T
Toda
Chitose
C
Hashizume
Kiyomatsu
K
Ueda
Koji
K
Kojima
Nakao
N
D004785:Environmental Pollutants / Q000633:toxicity; D004952:Esters / Q000737:chemistry / Q000633:toxicity; D008024:Ligands; D047493:PPAR alpha / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000187:drug effects* / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects / Q000378:metabolism; D010795:Phthalic Acids / Q000737:chemistry / Q000633:toxicity*
D004785:Environmental Pollutants; D004952:Esters; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D010795:Phthalic Acids