Urinary Elimination of Coproporphyrins Is Dependent on ABCC2 Polymorphisms and Represents a Potential Biomarker of MRP2 Activity in Humans
Figure 1
Proposed physiopathologic pathway for coproporphyrin elimination. This model was established on the basis of experimental data for both structure-affinity relationships for the interaction between coproporphyrin isomers and MRP2 [12] and of the measurement of coproporphyrin excretion in the bile and urine of Mrp2−/− or wild-type rats [6]. Calculations were based on an equimolar perfusion of coproporphyrin isomers in blood (for illustration, 10 molecules of each isomer are considered) and on the higher affinity of MRP2 for isomer I than for isomer III. The white squares represent molecules of isomer I and the black squares molecules of isomer III. Each part of the figure illustrates a particular situation: physiologic conditions (a); no MRP2 activity (b). R represents the UCP I/(I + III) ratio, calculated as the number of molecules of isomer I over the total number of molecules of isomer I and isomer III. In physiologic conditions (a), coproporphyrins enter the hepatocyte via an influx transporter, which may be OAT2, OATP1B1, OATP1B3, or another transporter. Coproporphyrins are then excreted predominantly in bile, via MRP2. As MRP2 has a higher affinity for isomer I than for isomer III due to a conformational advantage [12], the biliary coproporphyrin ratio is thus ~70% (67% in our theoretical example). A minor fraction may be secreted via BCRP and/or other transporters located in the canalicular membrane of hepatocytes. The fraction not excreted in bile returns to the blood via efflux transporters (possibly MRP3/ABCC3, which has a substrate specificity similar to or overlapping that of MRP2, MRP1/ABCC1, or MRP4/ABCC4, all located in the sinusoidal membrane; for review, see Borst et al. [26]). The remaining coproporphyrins (three times as much isomer III as isomer I) are excreted then in the urine via MRP2. The resulting UCP I/(I + III) ratio in normal subjects is thus ~30% (25% in our theoretical example). If MRP2 is entirely absent (b), as in DJS, only very small amounts of coproporphyrins are excreted in bile, probably via BCRP or other transporters. Most of the coproporphyrins are returned to the blood, presumably via MRP3, which is upregulated in Mrp2−/− mice [6, 27], or by MRP4. The kidney thus received both isomers, in equimolar proportions. Elimination in urine involves transporters other than MRP2 (possibly MRP4 or BCRP), with the same stereospecificity as MRP2 for the two isomers. According to this model, the urinary ratio should be about 80% (75% in our example), consistent with values observed in DJS patients.
