The infusion of
taurolithocholate (TLC) in vivo or in the isolated perfused liver of the rat causes
cholestasis and cellular
necrosis. In order to analyze the protective effect of
bile salts differing in number and steric position of their hydroxy groups against TLC-induced
cholestasis, isolated rat livers were perfused with
taurocholate (TC), taurohyocholate (
THC), tauroursocholate (TUC),
taurodehydrocholate (TDHC), and
tauroursodeoxycholate (TUDC) (16 and 32 mumol/l) with or without TLC (8 and 16 mumol/l). Bile flow,
bile salt secretion, and the hydroxylation pattern of the
bile salts secreted were analyzed. TLC caused complete
cholestasis after 15 min of perfusion. All
bile salts studied had a protective effect.
THC, TC, and TUDC completely abolished the
cholestasis induced by TLC while TUC did so only for the first 10 min. TDHC was protective only as long as it was biotransformed into hydroxyoxo
bile salts. Coinfusion of
bile salts did not influence uptake of TLC (greater than or equal to 93% of dose). Differences were found regarding the amount of TLC biotransformed (% of uptake): TC 50%;
THC 32%; TUDC 36%; TUC 20%. Light microscopy revealed cellular
necrosis, and dilated canaliculi were found in livers perfused with TLC only or in combination with TUC or TDHC, while the other
bile salts prevented these changes. We conclude that
bile salts with low
micelle-forming capacity have little protective effect against TLC-induced
cholestasis. These
bile salts induce less biotransformation of TLC than TC,
THC, and TUDC. The protective effect is not dependent on the hydrocholeretic effect of the added
bile salt and is not due to an uptake inhibition.