Bisphenols That Stimulate Cells To Release Alkali Metal Cations:  A Structure−Activity Study

Abstract

The laxative action of phenolphthalein (5) is believed to result from induction of potassium and water efflux from the colon epithelium. In cultured cells, K+ efflux is promoted by 5 and by a contaminant (1) present in commercial phenol red. Six compounds with chemical structures related to those of 5 and 1 were tested for ability to induce the release of 86Rb from COS-7 cells preloaded with this isotope: 4,4'-(9-fluorenylidene)diphenol (2), 4, 4'-(9-fluorenylidene)dianiline, 4, 4'-(9-fluorenylidene)bisphenoxyethanol, 1,1'-bi-2-naphthol, 4, 4'-biphenol, and bis(4-hydroxyphenyl)methane. With one exception these compounds were all inactive at a concentration of 10 microM. However, 2 caused profound 86Rb efflux at concentrations as low as 100 nM. Concentrations of 5 1-2 orders of magnitude higher were needed to achieve similar levels of activity. The three compounds known to be active in this experimental system share a common feature that is absent in all the inactive compounds: a five-membered ring structure, one of whose carbon atoms is disubstituted with p-hydroxyphenyl residues. Because 2 and 5 are readily available, comparative studies on the mechanism of action of these biphenols at the cellular level can now be undertaken.

Nitric Oxide Does Not Mediate Promotion of Cellular Potassium Release by Phenolphthalein in Cos‐7 Cells

“…When COS‐7 cells preloaded with 86 Rb + were incubated at 37°C in HBSS, 37% of the cell‐associated radioactivity was released into the culture medium within 10 min and a further 15% was released over the next 30 min (Table 1). These results indicate an initial loss of loosely associated radioactivity followed by a slow release of the remaining isotope, as seen previously 15 . When phenolphthalein (10 µmol/L) was also present in the incubation, these values increased to 64 and 22%, respectively, showing that phenolphthalein induces a rapid release of 86 Rb + (Table 1).…”

Regulation of 86Rb+ ion transport across polarized human colonocytes by bis‐phenolic compounds

“…A potential link between laxative action and K + efflux was established when the impurity in the pH indicator phenol red found to stimulate cellular K + release was subsequently identified as a structural homologue of the laxative phenolphthalein 6,16 . It was later established that a family of compounds related to phenolphthalein can stimulate K + efflux from different cell types 6,7 …”

“…6,16 It was later established that a family of compounds related to phenolphthalein can stimulate K + efflux from different cell types. 6,7 Previously, bis-phenolic compounds have been shown to affect Na + and K + transport of certain cell types, but not others. 6,9 Whether this selective action was due to membrane attributes or cell-specific intracellular factors is not known.…”

“…Bis‐phenolic compounds have been found to have a direct effect on K + ion efflux from cells in vitro . A series of experiments that started with characterizing cation transport changes in serum‐free medium culminated in the observation that phenolphthalein and a family of structurally related compounds cause rapid release of the K + ion homologue 86 Rb + from cultured cells 5–7 . The K + release was coupled with cellular influx of Na + ions, 8 indicating a possible link to the laxative action of these compounds.…”

NTP Research Report on Biological Activity of Bisphenol A (BPA) Structural Analogues and Functional Alternatives

“…Along with various other phenolic compounds, 4,4-BPF has been extracted from the Chinese medical herb Gastrodia elata Blume and has been evaluated as a smooth muscle relaxant 56; 161 an antiinflammatory 82 , and a platelet anti-aggregating agent 112 . Other miscellaneous effects explored include: the effects of BPS on rat hearts and isolated myocytes 46 , inhibition of the hypoxic response of human hepatoma cells 80 , and stimulation of cells to release alkali metal cations 62 .…”