Effect of ABCC2 (MRP2) Transport Function on Erythromycin Metabolism

The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for CYP3A4 activity. Using a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Since these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2-knockout mice, we found that erythromycin metabolism was significantly increased, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected by Abcc2 deficiency. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked with increased erythromycin metabolism, but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism independently of changes in CYP3A4 activity