Arachidonic acid as a possible modulator of estrogen, progestin, androgen, and glucocorticoid receptors in the central and peripheral tissues.
In an attempt to learn whether modulation of steroid hormone receptor by arachidonate is generalized or not, the arachidonate effect was examined in cytosol estrogen (ER), progestin (PR), androgen (AR) and glucocorticoid receptors (GCR) from the central and peripheral tissues of rats by sucrose density gradient centrifugation, and gel filtration on LH20 columns or dextran-coated charcoal absorption. Arachidonate and other long-chain fatty acids appear to inhibit the specific binding of estrogen ([3H]R2858), progestin ([3H]R5020), androgen ([3H]R1881) and glucocorticoid ([3H]dexamethasone) to the respective receptors in brain (neonatal cerebral cortex and hypothalamus-preoptic area, HPOA), uterus and prostate, with the exception of the potentiating effect on the brain estrogen receptors. The potency of the unsaturated fatty acids paralleled to some degree the number of cis double bonds and carbon, in that oleate (C18:1) arachidonate (C20:4) docosahexaenoate (C22:6). The arachidonate inhibition was dose-dependent in the tissue steroid hormone receptors, except for dose-dependent potentiation of the brain cortical estrogen receptors. Inhibitory potency as expressed by the concentration for 50% maximum inhibition (Ki) was in the range of 11-18 microM for the receptors other than the uterine estrogen receptors with the value of 44 microM, suggesting lower sensitivity for the estrogen receptor to the arachidonate effect in the uterus. Analysis on kinetics and Scatchard plot revealed the non-competitive type of the inhibition. In addition, arachidonate lowered dose-dependently the peak of labelled progestin or estrogen binding to the 8S receptor proteins, which were collected from fractions in the 8S region of the cytosols from intact or diethylstibestrol-primed rat uteri. These results suggest the generalized modulatory effect of arachidonate on the steroid hormone receptors in the central and peripheral tissues. Arachidonate could affect, negatively or positively, the estrogen receptors, and negatively the progestin, androgen and glucocorticoid receptors, through a possibly direct but weak binding at sites different from steroid binding sites on the receptor molecules. A potential messenger role of arachidonate itself has been implicated in the regulation or modulation of the steroid hormone receptors.
Kato
J
J
Department of Obstetrics and Gynecology, Yamanashi Medical University, Japan.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism*; D002499:Centrifugation, Density Gradient; D002540:Cerebral Cortex / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism; D007700:Kinetics; D008297:Male; D011301:Preoptic Area / Q000378:metabolism; D011467:Prostate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011944:Receptors, Androgen / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism*
D001095:Arachidonic Acids; D005230:Fatty Acids, Nonesterified; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D016718:Arachidonic Acid