Cholesterol-metabolizing cytochromes P450

By catalyzing the first steps in different pathways of cholesterol degradation, cytochromes P450 ( P450s) 7A1, 27A1, 11A1, and 46A1 play key roles in cholesterol homeostasis. CYP7A1 is a microsomal liver- specific enzyme that converts cholesterol to 7 alpha- hydroxycholesterol. CYP27A1 is a ubiquitously expressed mitochondrial P450 that metabolizes cholesterol to 27- hydroxycholesterol. CYP11A1 also resides in mitochondria but is expressed mainly in steroidogenic tissues, where it catalyzes the conversion of cholesterol to pregnenolone. Finally, CYP46A1 is a brain- selective microsomal monooxygenase producing 24S- hydroxycholesterol from cholesterol. Catalytic efficiencies of cholesterol- metabolizing P450s vary significantly and probably reflect physiological requirements of different organs for the rate of cholesterol turnover. P450s 7A1, 27A1, 11A1, and 46A1 represent a unique system for elucidation of how different enzymes have adapted to fit their specific roles in cholesterol elimination. Studies of cholesterol- metabolizing P450s suggest that their activities could be modulated post- translationally and that they should also be considered as targets for regulation of cholesterol homeostasis.