EFFECTS OF DIOSGENIN, A PLANT-DERIVED STEROID, ON BILE SECRETION AND HEPATOCELLULAR CHOLESTASIS INDUCED BY ESTROGENS IN THE RAT

Increased biliary secretion of cholesterol and lipid vesicles (unilame llae and multilamellae) induced by diosgenin (D), a plant-derived ster oid, has cytoprotective effects in the rat liver subjected to obstruct ive cholestasis. In this study, our aims were to investigate the follo wing: 1) the effects of D on the bile secretory process and on the cho lestasis induced by estradiol-17 beta-(beta-D-glucuronide) (E17G) or 1 7 alpha-ethynylestradiol(E) administration; 2) whether the potentially protective effects of D are related to D-induced increase of biliary cholesterol and lipid lamellae; and 3) whether D has other effects cap able of modifying specific bile secretory processes or preventing the cholestatic effects of estrogens. Rats were fed a standard ground chow (control group) or chow containing D for 6 days. E17G was administere d i,v, to control and D-fed rats and bile flow, bile salt output, and alkaline phosphatase excretion were examined. 17 alpha-E was administe red from days 4 to 6 to rats fed standard chow or chow plus D for 6 da ys and different functional parameters of the bile secretory process a s well as the ultrastructure of hepatocytes and histochemistry of alka line phosphatase and Mg2+-adenosine triphosphatase (ATPase:) were exam ined. D-treatment markedly increased cholesterol and lamellar structur es in bile and attenuated the acute cholestatic effects of E17G, D-fee ding prevented the decrease of taurocholate maximum secretory rate and the increase of biliary alkaline phosphatase and Ca2+,Mg2+-EctoATPase (EctoATPase) excretion, as well as the increase of cholesterol/ phosp holipids ratio, alkaline phosphatase activity, and EctoATPase content in canalicular plasma membranes induced by E, D-feeding did not preven t E-induced decrease of basal bile flow, bile salt, cholesterol, and p hospholipid secretory rates nor the decrease of Na+,K+-ATPase activity and Nac-taurocholate cotransporting polypeptide (Ntcp) content in iso lated sinusoidal membranes. Cholestatic alterations of canalicular dom ain were apparent in E-treated rats. D administration was also associa ted with changes of ultraestructure and histochemistry of hepatocytes, E-induced alterations in ultrastructure and acinar distribution and i ntensity of histochemical reaction of both enzymes were partially prev ented by D-feeding, We conclude that D administration, in addition to inducing a marked increase of biliary cholesterol and lipid lamellar s tructures output, was associated to changes in hepatocyte morphology a nd plasma membrane composition, enzymes activity, and histochemistry, D-feeding attenuated the acute cholestatic effects of E17G. D-induced increase of bile cholesterol and lipid lamellae content was not appare nt when D-fed rats received E. Despite this fact, D administration pre vented some cholestatic effects of E, probably through different metab olic effects and/or direct membrane effects, not related to increased lipid lamellae excretion.