RELATIONSHIP BETWEEN BILIARY LIPID AND PROTOPORPHYRIN SECRETION - POTENTIAL ROLE OF MDR2 P-GLYCOPROTEIN IN HEPATOBILIARY ORGANIC ANION TRANSPORT

Background/Aims: Erythropoietic protoporphyria, caused by ferrochelata se deficiency, leads to protoporphyrin accumulation in the liver. Ther apeutic attempts to increase the secretion of this hydrophobic organic anion into bile are hampered by a lack of understanding of the secret ory mechanism(s) involved. We have investigated biliary secretion of p rotoporphyrin in rats and mice, primarily targeted on the role of bili ary lipids in this process. Methods: Gel permeation chromatography was applied to investigate the association of porphyrins with lipid fract ions in bile. Secretion of endogenous porphyrins was studied in (GY mu tant) rats and mdr2 P-glycoprotein deficient mice, under conditions of widely varying biliary lipid secretion rates. Results: Gel permeation chromatography revealed that, in native human and rat bile, protoporp hyrin associated,vith cholesterol/phospholipid vesicles upon elution w ith bile salt-free buffer. In contrast, the more hydrophilic coproporp hyrin isomers I and III were found only in bile salt/organic anion hyb rid particles and smaller aggregates. Interruption of the enterohepati c circulation in normal Wistar rats resulted in a parallel decrease of endogenous protoporphyrin-, lipid-, and bile salt secretion, but did not alter the secretion of coproporphyrin I and III. Uncoupling of lip id- from bile salt secretion by sulfated taurolithocholate resulted in impaired secretion into bile of protoporphyrin only. Conversely, secr etion of coproporphyrin I and III, but not that of protoporphyrin, was impaired in mutant Groningen Yellow rats with defective ATP-dependent hepatobiliary organic anion transport. In mice homozygous for a disru ption of the mdr2 P-glycoprotein gene, resulting in complete absence o f phospholipids in bile and strongly reduced cholesterol output, secre tion of protoporphyrin was reduced by 90%, whereas that of coproporphy rin I and III was affected to a much lesser extent. Conclusions: Our d ata demonstrate a close association between protoporphyrin and lipid s ecretion into bile, indicating that these processes are, at least func tionally coupled. This finding implicates a role of mdr2 P-glycoprotei n activity in hepatobiliary removal of the hydrophobic organic anion p rotoporphyrin. Hence, it may be speculated that protoporphyrin secreti on can be influenced by drugs, diet or other means that affect biliary lipid secretion.