The relationships between bile acid structure, protoporphyrin load, and biliary protoporphyrin excretion were studied in rat livers perfused with 0 or 0.7 mumol/min taurocholate and protoporphyrin loads between 350 and 35,525 nmol. Bile acid treatment increased the excretion of extracted protoporphyrin from 0.4 to 28%, the maximal biliary protoporphyrin concentration 32-fold, the protoporphyrin excretion rate approximately 150-fold, and the coupling of excreted protoporphyrin to bile acid. Infusions (0.7 mumol/min) of bile acids differing in structure with 1,500 nmol protoporphyrin all significantly increased protoporphyrin excretion but ursodeoxycholate and tauroursodeoxycholate did so less than others. Infusions (0.175-1.4 mumol/min) of taurocholate, deoxycholate, ursodeoxycholate, and chenodeoxycholate confirmed that protoporphyrin excretion increased significantly more with taurocholate or deoxycholate than chenodeoxycholate and chenodeoxycholate more than ursodeoxycholate. The relative ineffectiveness of dihydroxylated bile acids with a hydroxy group at the seven position (alpha- or beta-configuration) was not correlated with physicochemical parameters of the bile acids and remains unexplained. The findings suggest that ursodeoxycholate is the least acceptable bile acid to consider as a potential treatment for protoporphyria.
Highly selective bile acid hydroxylation by the multifunctional bacterial P450 monooxygenase CYP107D1 (OleP)
