Effects of endocrine disruptors on the formation of prostaglandin and arachidonoyl-CoA formed from arachidonic acid in rabbit kidney medulla microsomes.
Under physiological conditions, small amounts of free arachidonic acid (AA) are released from membrane phospholipids, and cyclooxygenase (COX) and acyl-CoA synthetase (ACS) competitively act on this fatty acid to form prostaglandins (PGs) and arachidonoyl-CoA (AA-CoA). To explore the possible actions of endocrine disruptors on the metabolic fate of free AA into these two pathways, we investigated the effects of nonylphenol (NP), bisphenol A (BPA), di-n-butyl phthalate (DBP), benzyl-n-butyl phthalate (BBP) and di-2-ethylhexyl phthalate (DEHP) on the formation of PG and AA-CoA from 5 microM AA (close to the physiological concentration of the substrate) in rabbit kidney medulla microsomes. The kidney medulla microsomes were incubated with 5 microM [(14)C]-AA in 0.1 M Tris/HCl buffer (pH 8.0) containing cofactors of COX (reduced glutathione and hydroquinone) and cofactors of ACS (ATP, MgCl(2) and CoA). After incubation, PG (as total PGs) and AA-CoA were separated by selective extraction using petroleum ether and ethyl acetate. NP (1-200 microM) strongly enhanced the AA-CoA formation with a coincident decrease in the PG formation. BPA, DBP, BBP and DEHP failed to show any effect on the PG and AA-CoA formation up to 200 microM. Experiments utilizing 60 microM AA as the substrate concentration indicated that, under a low concentration of AA, NP decreases PG formation by inhibiting the COX activity, and reduces the AA flow into the COX pathway through inhibition on the COX activity, increasing availability of the substrate for the ACS and leading to enhanced AA-CoA formation. These results firstly show that NP has the potential to disturb the balance of PG and AA-CoA formations under normal physiological conditions.
Fujimoto
Yohko
Y
Department of Hygienic Chemistry, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan. fujimoto@gly.oups.ac.jp
Usa
Kumiko
K
Sakuma
Satoru
S
D000214:Acyl Coenzyme A / Q000096:biosynthesis*; D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D001559:Benzhydryl Compounds; D003993:Dibutyl Phthalate / Q000494:pharmacology; D004051:Diethylhexyl Phthalate / Q000494:pharmacology; D052244:Endocrine Disruptors / Q000494:pharmacology*; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D019800:Phenol / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010795:Phthalic Acids / Q000494:pharmacology; D011453:Prostaglandins / Q000096:biosynthesis*; D011817:Rabbits; D000098826:Bisphenol A Compounds
D000214:Acyl Coenzyme A; D000473:Alkanes; D016718:Arachidonic Acid; D001559:Benzhydryl Compounds; D003993:Dibutyl Phthalate; D004051:Diethylhexyl Phthalate; D052244:Endocrine Disruptors; D019800:Phenol; D010636:Phenols; D010795:Phthalic Acids; D011453:Prostaglandins; C026563:arachidonyl-coenzyme A; C025256:nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds; C017573:nonane; C027561:butylbenzyl phthalate