title: Effect of ABCC2 (MRP2) transport function on erythromycin metabolism.
abstract: The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because 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 Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.
authors: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: R M
authors: RM
authors: Franke
authors: C S
authors: CS
authors: Lancaster
authors: C J
authors: CJ
authors: Peer
authors: A A
authors: AA
authors: Gibson
authors: A M
authors: AM
authors: Kosloske
authors: S J
authors: SJ
authors: Orwick
authors: R H
authors: RH
authors: Mathijssen
authors: W D
authors: WD
authors: Figg
authors: S D
authors: SD
authors: Baker
authors: A
authors: A
authors: Sparreboom
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002460:Cell Line; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004917:Erythromycin / Q000378:metabolism*; D005260:Female; D014644:Genetic Variation / Q000187:drug effects / Q000502:physiology; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008874:Midazolam / Q000494:pharmacology; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D055815:Young Adult
chemical_list: D051544:Cytochrome P-450 CYP3A; D004917:Erythromycin; D008874:Midazolam; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C510163:CYP3A4 protein, human