Taurohyocholate, taurocholate, and tauroursodeoxycholate but not tauroursocholate and taurodehydrocholate counteract effects of taurolithocholate in rat liver

Abstract

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 ~tmol/1) with or without TLC (8 and 16 ~tmol/1). 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 (_> 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.

Prevention of Taurolithocholate-Induced Hepatic Bile Canalicular Distortions by HPLC-Characterized Extracts of Artichoke (Cynara scolymus) Leaves

“…An argument favouring this suggestion is provided by the fact that the bile canaliculi tend to be dilated, indicating some kind of choleretic action of the extracts, although dilatation of canaliculi was much more prominent in the absence of taurolithocholate. This interpretation is in line with recent observations in the isolated perfused rat liver made by Schölmerich et al [19] which led to the conclusion that the protective effect of different bile salts increases with increasing micelle-forming capacity. On the other hand, the choleretic effect of the extracts cannot be the only reason for their protection, since dehydrocholate was found to be incapable of reversing cholestasis in vivo, while taurocholate was capable [8], [20], although dehydrocholate is a superior choleretic.…”

Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat

“…Whatever the mechanism by which internalisation of Bsep occurs, factors known to stimulate insertion of this transporter into its membrane domain would be expected to help restore the insertion/internalisation balance, thus preventing disruption of its localisation; this was shown here to be the case for DB-cAMP (see fig 6). A similar phenomenon may explain the protective effect against TLC induced cholestasis and BS secretory failure of non-cholestatic BS-like taurocholate, 38 tauroursodeoxycholate, 20 38 39 which were both shown to stimulate vesicular Bsep targeting. 17 40 In addition to impaired Bsep localisation, other mechanisms by which TLC alters normal transport and/or retention of BS at the hepatocanalicular level should be considered, and may well act in concert, namely: (i) the decrease in CM fluidity induced by TLC 35 ; this may affect the functional BS transporter capacity, as has been shown to occur elsewhere for 14 C-TC transport in CM vesicles 41 ; (ii) impaired intracellular BS retention due to reduced binding to cytosolic proteins; reversible displacement of BS from their binding to glutathione Stransferase (ligandin) by TLC has been shown to occur, 42 and this may account for the increase in intrinsic constant of liver to plasma sinusoidal 14 C-TC efflux (r 21 ) (see table 1); (iii) disruption of tight junctional integrity induced by TLC; this was described under similar conditions both in vivo 43 and in IHRC, 44 and may cause BS to diffuse back to plasma across the leaky intercellular junctional complex, thus contributing to their decreased output.…”