Modulatory Effects of Unsaturated Fatty Acids on the Binding of Glucocorticoids to Rat Liver Glucocorticoid Receptors^*

Abstract

Binding of the synthetic glucocorticoid dexamethasone to the rat liver cytosol glucocorticoid receptor was inhibited by physiological concentrations of nonesterified fatty acids as a function of increasing dose, degree of unsaturation, and chain length of the fatty acid. Polyunsaturated fatty acids were the most potent inhibitors. Scatchard analysis and Line-weaver-Burk plots of the binding data revealed that both the association constants and number of binding sites decreased and that polyunsaturated fatty acids inhibition was of a mixed non-competitive type. The dissociation rate constant of [3H]dexamethasone from glucocorticoid receptors was increased by up to 10 times in the presence of docosahexaenoic acid, whereas a competitive inhibitor like the glucocorticoid antagonist RU 38486 had no effect. Moreover, sucrose density gradient analysis showed that docosahexaenoic acid inhibited the binding of [3H] dexamethasone to both the 8.8S and 4S forms. The results strongly suggest that unsaturated fatty acids are interacting at a site on the receptor different from the hormone binding site and the heat shock protein and that by binding to a second site unsaturated fatty acids greatly change the conformation of the hormone binding site to reduce its affinity for the hormone, either partially or completely depending on the concentration and the class of the fatty acid.

Gamma linolenic acid with tamoxifen as primary therapy in breast cancer

“…In addition, they raise the possibility of an additive or synergistic inhibitory effect of GLA with tamoxifen via enhanced down-regulation of ER-mediated growth. Our ER data are consistent with the previously identified modulatory properties of PUFA metabolites on steroid hormone receptors in various animal tissues (Clerc-Hoffman et al, 1983;Mitsuhashi et al, 1986Mitsuhashi et al, , 1988Vallette et al, 1991). Borras and Leclercq (1992) have demonstrated a dose-dependent down-regulatory effect of n-6 PUFA metabolites on growth and ER expression in the ER ϩ breast cancer cell line MCF-7.…”

“…Previous kinetic studies have implicated PUFAs to bind to a separate entity on the hormone receptor to the hormone binding site, thus inhibiting subsequent hormone-ligand binding via induction of a conformational change in the receptor molecule (Hwang, 1987;Kato, 1989;Vallette et al, 1991). Vallette et al (1988) in a detailed study investigated the influence of unsaturated fatty acids on the binding of estradiol to ERs in the uterine tissue of juvenile rats.…”

“…In vitro experiments have demonstrated PUFAs to inhibit the spreading and motility of cultured cancer cell lines and to up-regulate expression of the cell surface adhesion molecules E-cadherin and ␣-catenin (Jiang et al, 1998) which are thought to have anti-invasive and anti-metastatic properties. In addition, in vivo studies have shown PUFAs to be capable of exerting a modulatory influence on the structure and function of steroid hormone receptors, including the oestrogen receptor, in a variety of animal tissues (Clerc-Hoffman et al, 1983;Mitsuhashi et al, 1986Mitsuhashi et al, , 1988Vallette et al, 1991).…”

<b>Identification of the odor-active volatile compound (</b><i><b>Z</b></i><b>,</b><i><b>Z</b></i><b>)-4,7-tridecadienal as a potential ligand for the transmembrane receptor </b><b>CD36 </b>

“…1, namely B max decreased and K d increased with increasing concentrations of Z,Z-TDD (Table 2). A similar pattern of inhibition has been noted in prior studies, such as those on the inhibition of dexamethasone binding to glucocorticoid receptor by docosahexaenoic acid (28) and on that of anthraniloyl-7-methylguanosine triphosphate binding to the wheat germ translation initiation factor eIFiso4E by the genome-linked protein of the turnip mosaic virus (12). This is considered to be indicative of mixedtype competitive binding between two species of li- The B max (and the S.E.…”

Effect of dietary GLA+/?tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts

“…Previous kinetic studies have suggested that EFAs bind to a separate entity on the hormone receptor rather than to the hormone binding site, thus inhibiting subsequent ligand binding via induction of a conformational change in the receptor molecule. 18,19,33 Vallette and colleagues have demonstrated irreversible covalent binding of oestradiol to components of the ER protein in the presence of EFAs. 34 It is possible that in the presence of GLA a similar covalent bond is formed between tamoxifen and ER with resultant attenuation of receptor activity.…”