Vitamin D production in macrophages and PI interaction. The 25-hydrolylase CYP3A4 converts vitamin D into 25-(OH)D, its inactive form. To be active, the circulating 25-(OH)D is 1-α-hydroxylated by the renal or the extrarenal P450 cytochrome (CYP27B1) into 1,25-(OH)2D. Both 25-(OH)D and 1,25-(OH)2D can also be catabolized by 24-hydroxylation (CYP24A1) into 24,25-(OH)2D and 1α,24,25-(OH)2D respectively . Activated macrophages possess both CYP27B1 and CYP24A1 and are able to produce 1,25-(OH)2D locally at the site of inflammation. Protease inhibitors (PI) inhibit the function of the hepatic-CYP3A4 and the macrophage-CYP27B1 which are critical for active vitamin D synthesis, and exert a milder inhibition on the activity of the 24-hydroxylase (arrows). The net effect is a reduced production of 1,25-(OH)2D  that could influence immunity.