BRAIN BILIRUBIN CONTENT IS INCREASED IN P-GLYCOPROTEIN-DEFICIENT TRANSGENIC NULL MUTANT MICE

P-glycoprotein (P-gp), encoded by the mdr1a gene, is an ATP-dependent plasma membrane protein that is expressed in abundance on the blood-br ain barrier (BBB). P-gp limits the CNS influx and retention of a varie ty of lipophilic compounds. We hypothesized that brain bilirubin conte nt after an i.v. bilirubin infusion would be increased in P-gp-deficie nt mdr1a null mutant transgenic mice (mdr1a(-/-)) compared with contro ls. Eighteen mdr1a(-/-) null mutant and 18 P-gp-sufficient wild type m ice (+/+) were anesthetized and 50 mg/kg bilirubin infused through the tail vein. Brain bilirubin content (mean +/- SEM) 10 min after infusi on was significantly higher in mdr1a(-/-) (18.1 +/- 2.4 nmol/g) compar ed with (+/+) mice (10.4 +/- 1.0 nmol/g). Brain bilirubin content decl ined 60 min after infusion but remained higher in mdr1a(-/-) (10.3 +/- 1.4 nmol/g) compared with (+/+) mice (5.3 +/- 0.9 nmol/g). Brain bili rubin clearance did not differ between groups (t(1/2) similar to 55 mi n). We conclude that P-gp-deficient mdr1a(-/-) mice have significantly higher brain bilirubin content compared with controls after an i.v. b ilirubin load. These data suggest that I) bilirubin is a substrate for P-gp and 2) the increased brain bilirubin content in mdr1a(-/-) mice is due to enhanced brain bilirubin influx. We speculate that BBB P-gp provides a protective effect against bilirubin neurotoxicity by reduci ng brain bilirubin influx.