Cholesterol-metabolizing cytochromes P450: Implications for cholesterol lowering

Expert Opinion on Drug Metabolism and Toxicology

Volumn 4, Issue 11, 2008, Pages 1403-1414

  Pikuleva, Irina A ^a  

^a UNIVERSITY HOSPITALS OF CLEVELAND   (United States)

Author keywords

Cholesterol; Cholesterol homeostasis; Cholesterol lowering drugs; CYP27A1; CYP46A1; CYP7A1

Indexed keywords

3 HYDROXY 3 METHYLGLUTARYL COENZYME A; ANTILIPEMIC AGENT; AVASIMIBE; BILE ACID SEQUESTRANT; CHOLESTANETRIOL 26 MONOOXYGENASE; CHOLESTEROL; CHOLESTEROL 7ALPHA MONOOXYGENASE; CHOLESTEROL ACYLTRANSFERASE INHIBITOR; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; CYTOCHROME P450; CYTOCHROME P450 46A1; DIGOXIN; EZETIMIBE; FIBRIC ACID DERIVATIVE; FOLIC ACID; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LAPAQUISTAT; LIPID; NICOTINIC ACID; NONSTEROID ANTIINFLAMMATORY AGENT; PARACETAMOL; PHENACETIN; RANITIDINE; SIMVASTATIN; SQUALENE SYNTHASE INHIBITOR; TORCETRAPIB; TRIACYLGLYCEROL; UNCLASSIFIED DRUG; UNINDEXED DRUG; VERY LOW DENSITY LIPOPROTEIN; WARFARIN;

AGE; ATHEROSCLEROSIS; BLOATING; CARDIOVASCULAR DISEASE; CAUSE OF DEATH; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CONSTIPATION; DIABETES MELLITUS; DRUG ANTAGONISM; DRUG BINDING; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; ENZYME ACTIVITY; ERECTILE DYSFUNCTION; FLUSHING; GASTROINTESTINAL SYMPTOM; HOMEOSTASIS; HUMAN; HYPERCHOLESTEROLEMIA; HYPERTENSION; LIPID BLOOD LEVEL; LIVER TOXICITY; MONOTHERAPY; MUSCULOSKELETAL DISEASE; MYALGIA; NEUROLOGIC DISEASE; NONHUMAN; OBESITY; REVIEW; RHABDOMYOLYSIS; RISK FACTOR; SIDE EFFECT; SKIN MANIFESTATION; SMOKING; UNSPECIFIED SIDE EFFECT; WEAKNESS;

ANIMALS; ANTICHOLESTEREMIC AGENTS; ANTILIPEMIC AGENTS; CHOLESTEROL; CYTOCHROME P-450 ENZYME SYSTEM; HOMEOSTASIS; HUMANS; HYPERCHOLESTEROLEMIA; ISOENZYMES;

EID: 56749153371     PISSN: 17425255     EISSN: None     Source Type: Journal    
DOI: 10.1517/17425255.4.11.1403     Document Type: Review

References (117)

1. Data for 2003. Available from: http://www.cdc.gov/nccdphp/ overview_text.htm
2. Bjorkhem I. Crossing the barrier: oxysterols as cholesterol transporters and metabolic modulators in the brain. J Intern Med 2006;260(6):493-508
3. Norlin M, Wikvall K. Enzymes in the conversion of cholesterol into bile acids. Curr Mol Med 2007;7(2):199-218
4. Pikuleva IA. Cholesterol-metabolizing cytochromes P450. Drug Metab Dispos 2006;34(4):513-20
5. Pikuleva IA. Cytochrome P450s and cholesterol homeostasis. Pharmacol Ther 2006;112:761-73
6. Russell DW. The enzymes, regulation, and genetics of bile acid synthesis. Ann Rev Biochem, 2003;72:137-74
7. Chiang JY. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms. J Hepatol 2004;40(3):539-51
8. Repa JJ, Mangelsdorf DJ. The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Ann Rev Cell Dev Biol 2000;16:459-81
9. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106(25):3143-421
10. Grundy SM, Cleeman JI, Metz CN, et al. Implications ofrecent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110(2):227-39
11. Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High - Density Lipoprotein Intervention Trial. Am J Cardiol 2000;86(12A):19L-22L
12. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62(5):707-14
13. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26(5):1513-7
14. Forrester JS, Shah PK. Emerging strategies for increasing high-density lipoprotein. Am J Cardiol 2006;98(11):1542-9
15. Hokanson JE, Austin MA. Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies. J Cardiovasc Risk 1996;3(2):213-9
16. Bilheimer DW, Grundy SM, Brown MS, Goldstein JL. Mevinolin and colestipol stimulate receptor-mediated clearance of low density lipoprotein from plasma in familial hypercholesterolemia heterozygotes. Proc Natl Acad Sci USA 1983;80(13):4124-8
17. Davidson MH, Toth PP. Comparative effects of lipid-lowering therapies. Prog Cardiovasc Dis 2004;47(2):73-104
18. Liao JK, Laufs U. Pleiotropic effects of statins. Ann Rev Pharmacol Toxicol 2005;45:89-118
19. Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781-90
20. Shepherd J, Packard CJ, Bicker S, et al. Cholestyramine promotes receptor-mediated low-density-lipoprotein catabolism. N Engl J Med 1980;302(22):1219-22
21. Steinmetz KL. Colesevelam hydrochloride. Am J Health Syst Pharm 2002;59(10):932-9
22. Knopp RH. Drug treatment of lipid disorders. N Engl J Med 1999;341(7):498-511
23. Bays HE, Neff D, Tomassini JE, Tershakovec AM. Ezetimibe: cholesterol lowering and beyond. Expert Rev Cardiovasc Ther 2008;6(4):447-70
24. Sudhop T, Lutjohann D, Kodal A, et al. Inhibition of intestinal cholesterol absorption by ezetimibe in humans. Circulation 2002;106(15):1943-8
25. Florentin M, Liberopoulos EN, Elisaf MS. Ezetimibe-associated adverse effects: what the clinician needs to know. Int J Clin Pract 2008;62(1):88-96
26. Malik S, Kashyap ML. Niacin, lipids, and heart disease. Curr Cardiol Rep 2003;5(6):470-6
27. Gille A, Bodor ET, Ahmed K, Offermanns S. Nicotinic acid: pharmacological effects and mechanisms of action. Ann Rev Pharmacol Toxicol 2008;48:79-106
28. Brown BG, Zhao XQ, Chair A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345(22):1583-92
29. Bays H. Safety of niacin and simvastatin combination therapy. Am J Cardiol 2008;101(8A):3B-8B
30. Venkatesh PK, Caskey D, Reddy PC. Therapies to increase high-density lipoprotein cholesterol and their effect on cardiovascular outcomes and regression of atherosclerosis. Am J Med Sci 2008;336(1):64-8
31. Goldenberg I, Benderly M, Goldbourt U. Update on the use of fibrates: focus on bezafibrate. Vast: Health Risk Manag 2008;4(1):131-41
32. Staels B, Dallongeville J, Auwerx J, et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998;98(19):2088-93
33. Chapman MJ. Fibrates in 2003: therapeutic action in atherogenic dyslipidaemia and future perspectives. Atherosclerosis 2003;171(1):1-13
34. Backes JM, Gibson CA, Howard PA. Optimal lipid modification: the rationale for combination therapy. Vasc Health Risk Manag 2005;1(4):317-31
35. Meuwese MC, Franssen R, Stroes ES, Kastelein JJ. And then there were acyl coenzyme A: cholesterol acyl transferase inhibitors. Curr Opin Lipidol 2006;17(4):426-30
36. Van Leuven SI, Stroes ES, Kastelein JJ. High-density lipoprotein: a fall from grace? Ann Med 2008; 1-10
37. Elsayed RK, Evans JD. Emerging lipid-lowering drugs: squalene synthase inhibitors. Expert Opin Emerging Drugs 2008;13(2):309-22
38. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357(21):2109-22
39. Available from: http://www.clinicaltrials.gov
40. Myant NB, Mitropoulos KA. Cholesterol 7a-hydroxylase. J Lipid Res 1977;18:135-53
41. Pullinger CR, Eng C, Salen G, et al. Human cholesterol 7alpha-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 2002;110(1):109-17
42. The American Heart Association. Available from: http://www.americanheart.org/presenter.jhtml?identifier=183
43. Bjorkhem I, Reihner E, Angelin B, et al. On the possible use of the serum level of 7 alpha-hydroxycholesterol as a marker for increased activity of the cholesterol 7 alpha-hydroxylase in humans. J Lipid Res 1987;28(8):889-94
44. Nicolau VA, Shefer S, Salen G, Mosbach EH. Determination of hepatic cholesterol 7a-hydroxylase activity in man. J Lipid Res 1974;15:146-51
45. Reihner E, Angelin B, Rudling M, et al. Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients. J Lipid Res 1990;31(12):2219-26
46. Oda H, Yamashita H, Kosahara K, et al. Esterified and total 7 alpha-hydroxycholesterol in human serum as an indicator for hepatic bile acid synthesis. J Lipid Res 1990;31(12):2209-18
47. Hubacek JA, Bobkova D. Role of cholesterol 7alpha-hydroxylase (CYP7A1) in nutrigenetics and pharmacogenetics of cholesterol lowering. Mol Diagn Ther 2006;10(2):93-100
48. Bertolotti M, Abate N, Bertolotti S, et al. Effect of aging on cholesterol 7 alpha-hydroxylation in humans. J Lipid Res 1993;34(6):1001-7
49. Cheema SK, Cikaluk D, Agellon LB. Dietary fats modulate the regulatory potential of dietary cholesterol on cholesterol 7 alpha-hydroxylase gene expression. J Lipid Res 1997;38(2):315-23
50. Kurushima H, Hayashi K, Shingu T, et al. Opposite effects on cholesterol metabolism and their mechanisms induced by dietary oleic acid and palmitic acid in hamsters. Biochim Biophys Acta 1995;1258(3):251-6
51. Bravo E, Flora L, Cantafora A, et al. The influence of dietary saturated and unsaturated fat on hepatic cholesterol metabolism and the biliary excretion of chylomicron cholesterol in the rat. Biochim Biophys Acta 1998;1390(2):134-48
52. Lakshmanan MR, Veech RL. Short- and long-term effects of ethanol administration in vivo on rat liver HMG-CoA reductase and cholesterol 7alpha-hydroxylase activities. J Lipid Res 1977;18(3):325-30
53. Stahlberg D, Rudling M, Angelin B, et al. Hepatic cholesterol metabolism in human obesity. Hepatology 1997;25(6):1447-50
54. Wang J, Freeman DJ, Grundy SM, et al. Linkage between cholesterol 7alpha-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J Clin Invest 1998;101(6):1283-91
55. Couture P, Otvos JD, Cupples LA, et al. Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J Lipid Res 1999;40(10):1883-9
56. Hofman MK, Groenendijk M, Verkuijlen PJJH, et al. Modulating effect of the A-278 promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals. Eur J Hum Genet 2004;12:935-41
57. Abrahamsson A, Krapivner S, Gustafsson U, et al. Common polymorphisms in the CYP7A1 gene do not contribute to variation in rates of bile acid synthesis and plasma LDL cholesterol concentration. Atherosclerosis 2005;182:37-45
58. Hegele RA, Wang J, Harris SB, et al. Variable association between genetic variation in the CYP7 gene promoter and plasma lipoproteins in three Canadian populations. Atherosclerosis 2001;154(3):579-87
59. Hofman MK, Weggemans RM, Zock PL, et al. CYP7A1 A-278C polymorphism affects the response of plasma lipids after dietary cholesterol or cafestol interventions in humans. J Nutr Biochem 2004;134:2200-4
60. Kovar J, Suchanek P, Hubacek JA, Poledne R. The A-204C polymorphism in the cholesterol 7alpha-hydroxylase (CYP7A1) gene determines the cholesterolemia responsiveness to a high-fat diet. Physiol Res 2004;53(5):565-8
61. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. Interactions between common genetic polymorphisms in ABCG5/G8 and CYP7A1 on LDL cholesterol-lowering response to atorvastatin. Atherosclerosis 2004;175(2):287-93
62. Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. A promoter polymorphism in cholesterol 7alpha-hydroxylase interacts with apolipoprotein E genotype in the LDL-lowering response to atorvastatin. Atherosclerosis 2005;180(2):407-15
63. Einarsson K, Angelin B, Ewerth S, et al. Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 alpha-hydroxylase activity by isotope dilution-mass spectrometry. J Lipid Res 1986;27(1):82-8
64. Axelson M, Bjorkhem I, Reihner E, Einarsson K. The plasma level of 7 alpha-hydroxy-4-cholesten-3-one reflects the activity of hepatic cholesterol 7 alpha-hydroxylase in man. FEBS Lett 1991;284(2):216-8
65. Eusuftai S, Axelson M, Angelin B, Einarsson K. Serum 7 alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid malabsorption in patients with diarrhoea: correlation to SeHCAT test. Gut 1993;34(5):698-701
66. Sauter GH, Munzing W, Von Ritter C, Paumgartner G. Bile acid malabsorption as a cause of chronic diarrhea: diagnostic value of 7alpha-hydroxy-4-cholesten-3-one in serum. Dig Dis Sci 1999;44(1):14-9
67. Galman C, Arvidsson I, Angelin B, Rudling M. Monitoring hepatic cholesterol 7alpha-hydroxylase activity by assay of the stable bile acid intermediate 7alpha-hydroxy-4-cholesten-3-one in peripheral blood. J Lipid Res 2003;44(4):859-66
68. Loygren-Sandblom A, Heverin M, Larsson H, et al. Novel LC-MS/MS method for assay of 7alpha-hydroxy-4-cholesten-3-one in human plasma. Evidence for a significant extrahepatic metabolism. J Chromatogr B Analyt Technol Biomed Life Sci 2007;856(1-2):15-9
69. Duane WC, Javitt NB. 27-hydroxycholesterol: production rates in normal human subjects. J Lipid Res 1999;40(7):1194-9
70. Lund E, Andersson O, Zhang J, et al. Importance of a novel oxidative mechanism for elimination of intracellular cholesterol in humans. Arterioscler Thromb Vasc Biol 1996;16(2):208-12
71. Babiker A, Andersson O, Lund E, et al. Elimination of cholesterol in macrophages and endothelial cells by the sterol 27-hydroxylase mechanism. Comparison with high density lipoprotein-mediated reverse cholesterol transport. J Biol Chem 1997;272(42):26253-61
72. Song C, Liao S. Cholestenoic acid is a naturally occurring ligand for liver X receptor alpha. Endocrinology 2000;141(11):4180-4
73. Fu X, Menke JG, Chen Y, et al. 27-hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol-loaded cells. J Biol Chem 2001;276(42):38378-87
74. Bjorkhem I, Diczfalusy U. Oxysterols: friends, foes, or just fellow passengers? Arterioscler Thromb Vasc Biol 2002;22(5):734-42
75. Javitt NB. 25R,26-Hydroxycholesterol revisited: synthesis, metabolism, and biologic roles. J Lipid Res 2002;43(5):665-70
76. Bjorkhem I, Boberg KM, Leitersdorf E. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. In: Scriver AL, Beaudet al, Sly WS, editors, The metabolic and molecular bases of inherited disease. 7th edition. New York: McGraw-Hill; 1995. p. 2073-99
77. Lorincz MT, Rainier S, Thomas D, Fink JK. Cerebrotendinous xanthomatosis: possible higher prevalence than previously recognized. Arch Neurol 2005;62(9):1459-63
78. Genest J Jr, McNamara JR, Ordovas JM, et al. Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. J Am Coll Cardiol 1992;19(4):792-802
79. Shukla A, Sharma MK, Jain A, Goel PK. Prevention of atherosclerosis progression using atorvastatin in normolipidemic coronary artery disease patients - a controlled randomized trial. Indian Heart J 2005;57(6):675-80
80. Chen W, Chiang JY. Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha). Gene 2003;313:71-82
81. Ellis E, Axelson M, Abrahamsson A, et al. Feedback regulation of bile acid synthesis in primary human hepatocytes: evidence that CDCA is the strongest inhibitor. Hepatology 2003;38(4):930-8
82. Dietschy JM, Turley SD. Cholesterol metabolism in the brain. Curr Opin Lipidol 2001;12(2):105-12
83. Pfrieger FW. Outsourcing in the brain: do neurons depend on cholesterol delivery by astrocytes? Bioessays 2003;25(1):72-8
84. Vance JE, Hayashi H, Karten B. Cholesterol homeostasis in neurons and glial cells. Semin Cell Dev Biol 2005;16(2):193-212
85. Bjorkhem I, Lutjohann D, Diczfalusy U, et al. Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 1998;39(8):1594-600
86. Lutjohann D, Breuer O, Ahlborg G, et al. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci USA 1996;93(18):9799-804
87. Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA 1999;96(13):7238-43
88. Bjorkhem I, Andersson U, Ellis E, et al. From brain to bile. Evidence that conjugation and omega-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans. J Biol Chem 2001;276(40):37004-10
89. Heverin M, Bogdanovic N, Lutjohann D, et al. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease. J Lipid Res 2004;45(1):186-93
90. Kotti TJ, Ramirez DM, Pfeiffer BE, et al. Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci USA 2006;103(10):3869-74
91. Available from: www.alzforum.org
92. Chen W, Chen G, Head DL, et al. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab 2007;5(1):73-9
93. Cao G, Bales KR, Demattos RB, Paul SM. Liver X receptor-mediated gene regulation and cholesterol homeostasis in brain: relevance to Alzheimer's disease therapeutics. Curr Alzheimer Res 2007;4(2):179-84
94. Abildayeva K, Jansen PJ, Hirsch-Reinshagen V, et al. 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem 2006;281(18):12799-808
95. Brown J 3rd, Theisler C, Silberman S, et al. Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem 2004;279(33):34674-81
96. Famer D, Meaney S, Mousavi M, et al. Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the Apha-secretase pathway. Biochem Biophys Res Commun 2007;359(1):46-50
97. Ohyama Y, Meaney S, Heverin M, et al. Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): marked insensitivity toward different regulatory axes. J Biol Chem 2006;281(7):3810-20
98. Milagre I, Nunes MJ, Gama MJ, et al. Transcriptional regulation of the human CYP46A1 brain-specific expression by Sp transcription factors. J Neurochem 2008;106(2):835-49
99. Mast N, White MA, Bjorkhem I, et al. Crystal structures of substrate-bound and substrate-free cyrochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc Natl Acad Sci USA 2008;105(28):9546-51
100. Mast N, Norcross R, Andersson U, et al. Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 2003;42(48):14284-92
101. Hutzler JM, Hauer MJ, Tracy TS. Dapsone activation of CYP2C9-mediated metabolism: evidence for activation of multiple substrates and a two-site model. Drug Metab Dispos 2001;29(7):1029-34
102. Wester MR, Yano JK, Schoch GA, et al. The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0-A resolution. J Biol Chem 2004;279(34):35630-7
103. Locuson CW, Gannett PM, Ayscue R, Tracy TS. Use of simple docking methods to screen a virtual library for heteroactivators of cytochrome P450 2C9. J Med Chem 2007;50(6):1158-65
104. Liu KH, Kim MJ, Jung WM, et al. Lansoprazole enantiomer activates human liver microsomal CYP2C9 catalytic activity in a stereospecific and substrate-specific manner. Drug Metab Dispos 2005;33(2):209-13
105. Poulos TL, Johnson EF. Structures of cytochrome P450 enzymes. In: Montellano PROD, editor, Cytochrome P450: structure, mechanism, and biochemistry. 3rd edition. New York: Kluwer Academic/Plenum Publishers; 2005. p. 87-114
106. Williams PA, Cosine J, Sridhar V, et al. Mammalian microsomal cytochrome P450 monooxygenase: structural adaptations for membrane binding and functional diversity. Mol Cell 2000;5(1):121-31
107. Mast N, Liao W-L, Pikuleva IA, Turko IV. Mass spectrometry identification of membrane-interacting peptides suggests membrane topology of cytochrome P450 46A1 and NADPH-cytochrome P450 oxidoreductase (submitted). Arch Biochem Biophys 2008 [review]
108. Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol 2004;24(5):806-15
109. Wolozin B. Cholesterol and the biology of Alzheimer's disease. Neuron 2004;41(1):7-10
110. Reiss AB. Cholesterol and apolipoprotein E in Alzheimer's disease. Am J Alzheimers Dis Other Demen 2005;20(2):91-6
111. Carter CJ. Convergence of genes implicated in Alzheimer's disease on the cerebral cholesterol shuttle: APP, cholesterol, lipoproteins, and atherosclerosis. Neurochem Int 2007;50(1):12-38
112. Golomb BA, Criqui MH, White HL, Dimsdale JE. The UCSD Statin Study: a randomized controlled trial assessing the impact of statins on selected noncardiac outcomes. Control Clin Trials 2004;25(2):178-202
113. Guengerich FP. Human cytochrome P450 enzymes. In: Ortiz de Montellano PR, editor, Cytochrome P450. 3rd edition. New York, Boston, Dordrecht, London, Moscow: Kluwer Academic/Plenum Publishers; 2005. p. 377-530
114. Makishima M. Nuclear receptors as targets for drug development: regulation of cholesterol and bile acid metabolism by nuclear receptors. J Pharmacol Sci 2005;97(2):177-83
115. Michael LF, Schkeryantz JM, Burris TP. The pharmacology of LXR. Mini Rev Med Chem 2005;5(8):729-40
116. Available from: http://xray.bmc.uu.se/usf/voidoo.html
117. Available from: http://Ioschmidt.chemi.muni.cz/caver/online.php