Progesterone metabolism in human fibroblasts is independent of P-glycoprotein levels and Niemann-Pick type C disease

Progesterone inhibits intracellular transport of lysosomal cholesterol in c ultured cells, and thus at least in part mimics the biochemical phenotype o f Niemann-Pick type C disease (NPC) in human fibroblasts. The goal of this study was to determine whether metabolism of progesterone to other steroids is affected by the NPC mutation or by P-glycoprotein (a known progesterone target). We found that human fibroblasts metabolize progesterone in three steps: rapid conversion to 5 alpha-pregnane-3,20-dione, which is then reduc ed to 5 alpha-pregnane-3 beta(alpha)-ol-20-one with subsequent 6 alpha-hydr oxylation. The pattern and rates of progesterone metabolism were not signif icantly different in a variety of fibroblasts from normal individuals, NPC patients, and obligate heterozygotes. Inhibition of steroid 5 alpha-reducta se with finasteride completely blocked metabolism of progesterone but had n o effect on inhibition of LDL-stimulated cholesterol esterification (IC50 = 10 mu M). Progesterone also partially inhibited 25-hydroxycholesterol-indu ced cholesterol esterification, with similar dose-dependence in normal and NPC fibroblasts. P-glycoprotein levels varied significantly among the vario us fibroblasts tested, but no correlation with NPC phenotype or rate of pro gesterone metabolism was noted, and P-glycoprotein inhibitors did not affec t conversion of progesterone to products. These results indicate that metab olism of progesterone in human fibroblasts is largely independent of its ab ility to interfere with cholesterol traffic and P-glycoprotein function. (C ) 1999 Elsevier Science Ltd. All rights reserved.