title: HIV-1 protease inhibitor ritonavir potentiates the effect of 1,25-dihydroxyvitamin D3 to induce growth arrest and differentiation of human myeloid leukemia cells via down-regulation of CYP24.
abstract: HIV-1 protease inhibitor, ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explored the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to its inactive form 1,24,25,(OH)(3). Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)(2)D(3) induced expression of CYP24, and pre-incubation of these cells with RTV decreased this transcripts, resulting in increased intracellular levels of 1,25(OH)(2)D(3) and potentiation of the ability of 1,25(OH)(2)D(3) to induce growth arrest and differentiation of these cells. Taken together, inhibition of CYP24 might open a new paradigm for therapy using Vitamin D compounds.
authors.affiliation: Department of Hematology and Respiratory Disease, KMS, Kochi University, Okohcho, Kochi 783-8505, Japan. ikezoet@med.kochi-ms.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.forename: Kentaro
authors.initials: K
authors.lastname: Bandobashi
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Seisho
authors.initials: S
authors.lastname: Takeuchi
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sekiguchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakai
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Hirokuni
authors.initials: H
authors.lastname: Taguchi
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D019438:Ritonavir / Q000494:pharmacology*; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D017320:HIV Protease Inhibitors; D018950:Lipopolysaccharide Receptors; D013481:Superoxides; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D019438:Ritonavir