Effect of tauroursodeoxycholate and S-adenosyl-L-methionine on 17beta-estradiol glucuronide-induced cholestasis.
OBJECTIVE
S-adenosyl-L-methionine (SAMe) and tauroursodeoxycholate (TUDC) exert an additive ameliorating effect on taurolithocholate (TLC)-induced cholestasis. The aims were to investigate the protective effect of SAMe on 17beta-estradiol-glucuronide (17betaEG) cholestasis and to find out whether SAMe and TUDC may exert an additive, ameliorating effect.


METHODS
Hepatocyte couplet function was assessed by canalicular vacuolar accumulation (cVA) of cholyllysylfluorescein (CLF). Cells were co-treated with 17betaEG and SAMe, TUDC, or both (protection study), or treated with 17betaEG and then with SAMe, TUDC or both (reversion study) before CLF uptake. Couplets were also co-treated with SAMe and dehydroepiandrosterone (DHEA), a competitive substrate for the sulfotransferase involved in 17betaEG detoxification. The effects of 17betaEG, SAMe and TUDC were also examined on intracellular distribution of F-actin.


RESULTS
Both SAMe and TUDC significantly protected against, and reversed, 17betaEG-induced cholestasis, but their effects were not additive. DHEA abolished the protective effect of SAMe. 17BetaEG did not affect the uptake of CLF into hepatocytes at the concentrations used, and also, it did not affect the intracellular distribution of F-actin.


CONCLUSIONS
17BetaEG does not affect the uptake of CLF into hepatocytes. SAMe and TUDC protect and reverse 17betaEG-induced cholestasis, but without an additive effect. Protection by SAMe may involve facilitating the sulfation of 17betaEG.
Milkiewicz
P
P
Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK.
Roma
M G
MG
Cardenas
R
R
Mills
C O
CO
Elias
E
E
Coleman
R
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002779:Cholestasis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control*; D002793:Cholic Acids / Q000493:pharmacokinetics; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000633:toxicity; D005452:Fluoresceins / Q000493:pharmacokinetics; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000494:pharmacology*; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000199:Actins; D002793:Cholic Acids; D005452:Fluoresceins; C072313:cholyl-lysylfluorescein; C025483:estradiol-17 beta-glucuronide; D003687:Dehydroepiandrosterone; D004958:Estradiol; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D012436:S-Adenosylmethionine