Minireview CHOLESTEROL - METABOLIZING CYTOCHROMES P 450

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 -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. In mammals, excess cholesterol (5-cholestene-3 -ol) is removed mainly through conversion to bile acids, and only a small portion is used for production of steroid hormones (Turley and Dietschy, 1982). Enzymes called cytochromes P450 (P450s) initiate all quantitatively significant pathways of cholesterol degradation. The P450 proteins contain a single heme group and have a characteristic absorption at 450 nm when reduced and form a complex with CO (for recent reviews on P450s, see references: Nebert and Russell, 2002; Meunier et al., 2004; Aguiar et al., 2005; Coon, 2005; Denisov et al., 2005; Guengerich, 2005; Johnson and Stout, 2005). P450s from different families share low sequence identity ( 40%); nevertheless, they have a similar overall structural fold and generally carry out monooxygenation reactions (Graham and Peterson, 1999). This review describes only those P450s that act directly on cholesterol (Fig. 1); information about P450s that hydroxylate cholesterol derivatives can be found in other reviews (Russell, 2003; Payne and Hales, 2004). Furthermore, the major focus will be on human enzymes because some interspecies differences exist both in maintenance of cholesterol homeostasis and in the regulation of the activity of cholesterol-metabolizing P450s. Physiological and Medical Significance of CholesterolMetabolizing P450s CYP7A1. There are several metabolic routes that lead to the formation of bile acids and only one pathway to produce steroid hormones. In the liver, the main organ for cholesterol degradation, bile acid biosynthesis, is initiated and controlled by a liver-specific enzyme, CYP7A1, that converts cholesterol to 7 -hydroxycholesterol (Myant and Mitropoulos, 1977). This reaction represents the first and rate-limiting step in the classical or neutral bile acid biosynthetic pathway, which dominates under normal physiological conditions. Approximately 400 to 600 mg of cholesterol are eliminated through this pathway on a daily basis by the human liver (Sabine, 1977; Turley and Dietschy, 1982). Humans lacking cholesterol 7 -hydroxylase activity as a result of the mutation in the CYP7A1 gene have significant elevation of total and LDL cholesterol levels, substantial accumulation of cholesterol in the liver, and a markedly decreased rate of bile acid excretion (Pullinger et al., 2002). Increased plasma LDL cholesterol levels are also observed in some subjects carrying nucleotide substitutions in the CYP7A1 promoter region and, presumably, having reduced cholesterol 7 -hydroxylase activity (Wang et al., 1998). In two population studies, a frequent A-204C polymorphism ( 38–46% of the population carries the -204C allele) was found to have significant or modest effect on LDL cholesterol levels (Wang et al., 1998; Couture et al., 1999), whereas in three studies, the effect was inconsistent or nonsignificant (Hegele et al., 2001; Kovar et al., 2004; Abrahamsson et al., 2005). Thus, different results in the five studies are explained by differences in diet and in genetic background of the population. In addition to a medical significance, it is possible that the A-204C genotype has a pharmacological relevance because it was shown to be associated with a poor response to a cholesterollowering drug, atorvastatin, and to influence the response of plasma lipids to increased intake of dietary cholesterol and cafestol (Hofman et al., 2004; Kajinami et al., 2005). CYP27A1. Analysis of the CYP7A1 gene knockout mice and then Studies in the author’s laboratory described in this paper are supported by National Institutes of Health Grants GM62882 and AG024336. Article, publication date, and citation information can be found at http://dmd.aspetjournals.org. doi:10.1124/dmd.105.008789. ABBREVIATIONS: P450, cytochrome P450 enzyme; LDL, low-density lipoprotein; LXR, liver X receptor; CTX, cerebrotendinous xanthomatosis; ER, endoplasmic reticulum; PL, phospholipid; SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid. 0090-9556/06/3404-513–520$20.00 DRUG METABOLISM AND DISPOSITION Vol. 34, No. 4 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 8789/3100642 DMD 34:513–520, 2006 Printed in U.S.A. 513 at A PE T Jornals on Jauary 7, 2018 dm d.aspurnals.org D ow nladed from