title: The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo.
abstract: Cholesterol 24S-hydroxylase (CYP46A1) is of key importance for cholesterol homeostasis in the brain. This enzyme seems to be resistant toward most regulatory factors and at present no drug effects on its activity have been described. The crystal structures of the substrate-free and substrate-bound CYP46A1 were recently determined (Mast et al., Crystal structures of substrate-bound and substrate-free cytochrome P450 46A1, the principal cholesterol hydroxylase in the brain. Proc. Natl. Acad. Sci. USA. 2008. 105: 9546-9551). These structural studies suggested that ligands other than sterols can bind to CYP46A1. We show here that the antifungal drug voriconazole binds to the enzyme in vitro and inhibits CYP46A1-mediated cholesterol 24-hydroxylation with a Ki of 11 nM. Mice treated with daily intraperitoneal injections of voriconazole for 5 days had high levels of voriconazole in the brain and significantly reduced brain levels of 24S-hydroxycholesterol. The levels of squalene, lathosterol, and HMG-CoA reductase mRNA were reduced in the brain of the voriconazole-treated animals as well, indicating a reduced cholesterol synthesis. Most of this effect may be due to a reduced utilization of cholesterol by CYP46A1. One of the side-effects of voriconazole is visual disturbances. Because CYP46A1 is also expressed in the neural retina, we discuss the possibility that the inhibition of CYP46A1 by voriconazole contributes to these visual disturbances.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Huddinge, Sweden.
authors.forename: Marjan
authors.initials: M
authors.lastname: Shafaati
authors.forename: Natalia
authors.initials: N
authors.lastname: Mast
authors.forename: Olof
authors.initials: O
authors.lastname: Beck
authors.forename: Rima
authors.initials: R
authors.lastname: Nayef
authors.forename: Gun Young
authors.initials: GY
authors.lastname: Heo
authors.forename: Linda
authors.initials: L
authors.lastname: Björkhem-Bergman
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Irina A
authors.initials: IA
authors.lastname: Pikuleva
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002417:Cattle; D002784:Cholesterol / Q000378:metabolism; D000072556:Cholesterol 24-Hydroxylase; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D006888:Hydroxycholesterols; D011743:Pyrimidines; D012333:RNA, Messenger; D014230:Triazoles; C044563:24-hydroxycholesterol; C001521:lathosterol; D002784:Cholesterol; D013250:Steroid Hydroxylases; D000072556:Cholesterol 24-Hydroxylase; D065819:Voriconazole