Potential role of trans-inhibition of the bile salt export pump by progesterone metabolites in the etiopathogenesis of intrahepatic cholestasis of pregnancy.
OBJECTIVE
Progesterone metabolites such as 5alpha-pregnan-3alpha-ol-20-one (PM4) are elevated in serum of women with intrahepatic cholestasis of pregnancy (ICP).


RESULTS
When assayed in isolated perfused rat liver, PM4 did not induce cholestasis, whereas sulfated PM4 (PM4-S), which unlike PM4 is secreted into bile, reduced bile flow and bile acid (BA) output. Whether PM4-S inhibited the bile salt export pump (BSEP) was investigated. Radiolabeled methylesters (ME) of cholic acid and chenodeoxycholic acid were taken up by Xenopus laevis oocytes co-expressing rat BSEP and human carboxylesterase-1 (CES1), efficiently hydrolyzed to free BAs by CES1 and subsequently exported by BSEP. Rifampicin or cyclosporin A in the extracellular medium had no effect on BA efflux. In contrast, estradiol 17beta-D-glucuronide and several progesterone metabolites, including PM4-S, induced a marked non-competitive trans-inhibition of BSEP-mediated BA efflux (Ki=20-60 microM). Mitochondrial activity was markedly impaired in oocytes incubated with BA-MEs, but not with free BAs. Co-expression of CES1 and BSEP partly protected oocytes from this toxic effect. Trans-inhibition of BSEP abolished this protection.


CONCLUSIONS
Several estrogens and progesterone metabolites are able to induce trans-inhibition of BSEP and the subsequent toxicity induced by the accumulation of BAs, which may play a role in the etiopathogenesis of ICP.
Vallejo
Marta
M
Laboratory of Experimental Hepatology and Drug Targeting, University of Salamanca, Salamanca, Spain.
Briz
Oscar
O
Serrano
Maria A
MA
Monte
Maria J
MJ
Marin
Jose J G
JJ
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000503:physiopathology*; D019826:Cholic Acid / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000494:pharmacology*; D014982:Xenopus laevis
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D001647:Bile Acids and Salts; D013256:Steroids; D011374:Progesterone; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; D019826:Cholic Acid