ROLE OF MULTIDRUG-RESISTANCE P-GLYCOPROTEINS IN CHOLESTEROL ESTERIFICATION

Cholesterol esterification, catalyzed by acyl-CoA:cholesterol acyltran sferase (ACAT), plays a central role in cellular cholesterol homeostas is and in physiologic processes that lead to coronary heart disease. A lthough ACAT resides in the endoplasmic reticulum (ER), the cholestero l substrate for esterification originates in the plasma membrane and m ust be transported to the ER for esterification. Progesterone inhibits esterification, possibly by blocking the transport of cholesterol to the ER. Recent studies suggest that progesterone acts by inhibiting th e activity of one or more of the multidrug-resistant (MDR) P-glycoprot eins. In the current manuscript, we demonstrate that progesterone's ab ility to inhibit esterification is not mediated through the progestero ne receptor. We evaluate a series of steroid hormones and find a stron g correlation between a steroid hormone's hydrophobicity and its abili ty to inhibit both cholesterol esterification and MDR catalyzed drug e fflux. We also find that cholesterol esterification is inhibited by no nsteroidal MDR inhibitors, and that this inhibition specifically affec ts the esterification of cholesterol derived from the plasma membrane. MDR inhibitors also inhibit cholesterol esterification in a wide rang e of cultured human cell lines. These observations suggest that MDR ac tivity normally functions in a general process of intracellular choles terol transport.