Phalloidin causes severe liver damage characterized by marked
cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the
bile acid derivative BALU-1, which does not inhibit the
sodium-dependent
bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of
phalloidin without impairing endogenous
bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than
taurocholic acid (TCA).
Phalloidin administration decreased basal (-60%) and TCA-stimulated bile flow (-55%) without impairing
bile acid output.
Phalloidin-induced
cholestasis was accompanied by liver
necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals,
phalloidin-induced
cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion (<5%) of tauro-BALU-1 was detected. BALU-1 did not inhibit the biliary secretion of endogenous
bile acids. When highly choleretic
bile acids, - ursodeoxycholic (UDCA) and
dehydrocholic acid (DHCA) - were administered, they were found less efficient than BALU-1 in preventing
phalloidin-induced
cholestasis. Biliary
phalloidin elimination was low but it was increased by BALU-1>TCA>DHCA>UDCA. In conclusion, BALU-1 is able to protect against
phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.