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 (unilamellae and multilamellae) induced by diosgenin (D), a plant-derived steroid, has cytoprotective effects in the rat liver subjected to obstructive cholestasis. In this study, our aims were to investigate the following: 1) the effects of D on the bile secretory process and on the cholestasis induced by estradiol-17beta-(beta-D-glucuronide) (E17G) or 17 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 capable 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 administered i.v. to control and D-fed rats and bile flow, bile salt output, and alkaline phosphatase excretion were examined. 17alpha-E was administered from days 4 to 6 to rats fed standard chow or chow plus D for 6 days and different functional parameters of the bile secretory process as well as the ultrastructure of hepatocytes and histochemistry of alkaline phosphatase and Mg2+-adenosine triphosphatase (ATPase) were examined. D-treatment markedly increased cholesterol and lamellar structures in bile and attenuated the acute cholestatic effects of E17G. D-feeding 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/ phospholipids ratio, alkaline phosphatase activity, and EctoATPase content in canalicular plasma membranes induced by E. D-feeding did not prevent E-induced decrease of basal bile flow, bile salt, cholesterol, and phospholipid secretory rates nor the decrease of Na+,K+-ATPase activity and Na+-taurocholate cotransporting polypeptide (Ntcp) content in isolated sinusoidal membranes. Cholestatic alterations of canalicular domain were apparent in E-treated rats. D administration was also associated with changes of ultrastructure and histochemistry of hepatocytes. E-induced alterations in ultrastructure and acinar distribution and intensity of histochemical reaction of both enzymes were partially prevented by D-feeding. We conclude that D administration, in addition to inducing a marked increase of biliary cholesterol and lipid lamellar structures output, was associated to changes in hepatocyte morphology and 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 apparent when D-fed rats received E. Despite this fact, D administration prevented some cholestatic effects of E, probably through different metabolic effects and/or direct membrane effects, not related to increased lipid lamellae excretion.
Accatino
L
L
Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago de Chile.
Pizarro
M
M
Solís
N
N
Koenig
C S
CS
D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000139:chemically induced*; D004144:Diosgenin / Q000494:pharmacology*; D004958:Estradiol; D004967:Estrogens; D004997:Ethinyl Estradiol; D006651:Histocytochemistry; D008099:Liver / Q000201:enzymology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013256:Steroids / Q000494:pharmacology*
D004967:Estrogens; D010936:Plant Extracts; D013256:Steroids; D004997:Ethinyl Estradiol; D004958:Estradiol; D004144:Diosgenin