Epoxy derivatives of arachidonic acid are potent stimulators of prolactin secretion.
Arachidonic acid is metabolized to three distinct classes of metabolites: cyclooxygenase produces prostaglandins, prostacyclins, and thromboxanes; lipoxygenase produces hydroperoxyeicosatetraenoic acids and, epoxygenase, a NADPH-dependent cytochrome P-450 enzyme, produces epoxyeicosatrienoic acids. Addition of 5,6-epoxyeicosatrienoic acid (5,6-EET) to GH3 cells, a rat anterior pituitary cell line, produces a rapid, dose-dependent stimulation of prolactin (PRL) release. Incubation with arachidonic acid (AA) was ineffective at increasing PRL release. The lipoxygenase metabolite 5-hydroxyeicosatetraenoic acid (5-HETE), however, increased PRL release from GH3 cells but with a much lower maximal response than 5,6-EET. We examined the role of metabolism inhibitors in 5,6-EET-mediated PRL release. Microsomal and cytosolic epoxide hydrolase (EH) inhibitors do not alter 5,6-EET-induced PRL release, suggesting that EH does not play a significant role in 5,6-EET mediated PRL release from GH3 cells. A chemical analog of 5,6-EET wherein the epoxide oxygen is replaced with a sulfur to afford 5,6-thioepoxyeicosatrienoic acid was also tested and found to stimulate the release of PRL, although not to the same extent as 5,6-EET. Although 5-HETE tends to increase PRL release from GH3 cells, 5,6-EET is significantly more potent at the stimulation of PRL release from GH3 cells.
Cashman
J R
JR
Department of Pharmaceutical Chemistry, University of California, San Francisco.
Hanks
D
D
Weiner
R I
RI
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D002460:Cell Line; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D004852:Epoxy Compounds / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000187:drug effects / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D051381:Rats
D001095:Arachidonic Acids; D004852:Epoxy Compounds; D006893:Hydroxyeicosatetraenoic Acids; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; D011388:Prolactin; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid