title: Organic anion transporting polypeptide (OATP)-mediated transport of coproporphyrins I and III.
abstract: 1. Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are polyspecific transporters that mediate the transport of organic acids into hepatocytes. Inactivating mutations of both OATP1B1 and OATP1B3 alleles lead to Rotor syndrome, a disease characterized by coproporphyrinuria, an elevated urinary excretion of coproporphyrins I and III. It was hypothesized that transport of coproporphyrins I and III was mediated by OATP1B1 and OATP1B3. 2. This hypothesis was tested using cells transfected with OATP1B1 and OATP1B3. OATP1B-mediated transport of coproporphyrin was time-dependent and concentration-dependent. OATP1B1-mediated transport of coproporphyrins I and III (Km = 0.13 and 0.22 µM, respectively), as did OATP1B3 (Km = 3.25 and 4.61 µM, respectively). The OATP1B-mediated transport of each coproporphyrin was inhibited by rifampicin. 3. The specificity of coproporphyrin transport was also investigated where OATP2B1 demonstrated meaningful transport of coproporphyrin III (Km = 0.31 µM), while OCT1, OCT2, OAT1, OAT3 and NTCP were negative for coproporphyrin transport. 4. The identification of coproporphyrins as OATP substrates in vitro more clearly defines the role of OATPs in the hepatic disposition and renal excretion of coproporphyrins I and III and provides compelling evidence for future in vivo exploration of coproporphyrins as biomarkers of OATP activity.
authors.affiliation: a Department of Metabolism and Pharmacokinetics , Novartis Institutes for BioMedical Research , Cambridge , MA , USA.
authors.forename: Dallas
authors.initials: D
authors.lastname: Bednarczyk
authors.affiliation: a Department of Metabolism and Pharmacokinetics , Novartis Institutes for BioMedical Research , Cambridge , MA , USA.
authors.forename: Carri
authors.initials: C
authors.lastname: Boiselle
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001692:Biological Transport; D015415:Biomarkers / Q000378:metabolism; D016466:CHO Cells; D003306:Coproporphyrins / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D057809:HEK293 Cells; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000378:metabolism; D027381:Liver-Specific Organic Anion Transporter 1; D013058:Mass Spectrometry; D009154:Mutation; D027361:Organic Anion Transporters / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism; D012293:Rifampin / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D015415:Biomarkers; D003306:Coproporphyrins; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; C026971:coproporphyrin III; D012710:Serum Albumin, Bovine; C031467:coproporphyrin I; D012293:Rifampin
keywords: Coproporphyrin; drug interaction; hyperbilirubinemia; organic anion transporting polypeptide; rotor syndrome