Decreased hepatic accumulation and enhanced esterification of cholesterol in mice deficient in mdr1a and mdr1b P-glycoproteins

Class I P-glycoproteins [Pgp; MDR1 (ABCB1) in humans, mdr1a and mdr1b in mi ce] confer resistance to structurally diverse chemotherapeutic drugs in cul tured cells and intact animals, but the function of these proteins in norma l physiology remains poorly characterized. Based on studies in cell culture , a putative role for class I Pgp in absorption and intracellular trafficki ng of sterols has been proposed. We examined wild-type and mdr1a(-/-)/1b(-/ -) mice to determine whether class I Pgp affects cholesterol absorption and esterification in vivo. Using a dual-isotope protocol, absorption of orall y administered radiolabeled cholesterol into serum did not differ between w ild-type and mdr1a(-/-)/1b(-/-) mice, demonstrating that class I Pgp is not essential for overall absorption of cholesterol through the intestine. How ever, the ratio of oral to intravenous labeled cholesterol in liver was dec reased significantly in mdr1a(-/-)/1b(-/-) mice. In the liver, but not othe r tested organs, deletion of class I Pgp enhanced kinetics of esterificatio n of an oral bolus of radiolabeled cholesterol without affecting esterifica tion of cholesterol administered intravenously. Steady-state hepatic conten t of cholesterol and esterified cholesterol also were unaffected by absence of mdr1a and mdr1b. Thus, in normal animals, class I Pgp functions to kine tically increase hepatic accumulation and decrease esterification of orally administered cholesterol in vivo.