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Genistein's Mechanism(s) Of Action On Intestinal Chloride Secretion In Mice

The major route for cAMP‐mediated chloride (Cl) secretion across the intestinal epithelial apical membrane is presumed to be via CFTR, a chloride channel widely known to be activated in vitro by genistein. We have shown that daily injections of genistein (600mg/kg body weight, 600G) mediate significant increases in intestinal Cl secretion (Isc) in male mice after 2 weeks and female mice after one week, when compared to control (0G). This study aimed to determine whether genistein‐induced increases in intestinal Cl secretion were attributed to; (a) changes in CFTR protein expression using standard western blot techniques and, (b) changes in intracellular signaling mechanisms using basolateral application of: MDL‐12330A (an adenylate cyclase inhibitor), KT‐5720 (a PKA inhibitor), LY‐294002 (a PI3K inhibitor) and PD‐98059 (a MAPK inhibitor). We found no effect of 1μM KT‐5720, 20μM LY‐294002 or 10μM PD‐98059 on the basal or steady‐state forskolin‐stimulated Isc in 600G male or female mice. MDL‐12330A (10μM)) significantly reduced basal Isc in 600G females from 215.8±12.6 μA/cm2 (n=15) to 157.0±21.5 μA/cm2 (n=8, P<0.05) and decreased steady‐state forskolin‐stimulated Isc from 101.8±17.5 μA/cm2 (n=15), to 35.6±8.3 μA/cm2 (n=8, P<0.05), but was without effect in 600G males. Total CFTR protein expression normalized to total actin protein expression was unchanged in jejunum removed from any groups. These data suggest that the genistein‐mediated increases in intestinal Isc; (a) are not mediated via changes in intestinal CFTR protein expression in male or female mice and, (b) are mediated by adenylate cyclase in female but not male mice. RS and SS were supported by the Midwestern University Summer Fellowship Program. LA was supported by NIH (1R15DK071625‐01A2).