title: HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D.
abstract: BACKGROUND
  A high prevalence of bone demineralization occurs in people living with HIV/AIDS. The contribution of HIV itself and its treatment is still unclear. Protease inhibitors (PIs) are potent inhibitors of the cytochrome p450 enzyme system. Three cytochrome p450 mixed function oxygenases control serum levels of 1,25-dihydroxyvitamin D (1,25(OH) D ), which is responsible for vitamin D actions in target tissues including bone. The 25- and 1alpha-hydroxylases regulate 1,25(OH) D synthesis and 24-hydroxylase 1,25(OH) D catabolism.
  
  
  OBJECTIVE
  To assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair the activity of the main enzymes involved in 1,25(OH) D homeostasis.
  
  
  METHODS
  Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP-1) cell lines, expressing 25-hydroxylase and 1alpha-hydroxylase, respectively. The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH) D. Conversion rates of vitamin D to 25-hydroxyvitamin D [25(OH)D ]; 25(OH)D to 1,25(OH) D or 24,25(OH) D, and 1,25(OH) D degradation were quantified in untreated and HIV-PI-treated cells after C -cartridge extraction and high-performance liquid chromatography purification of 25(OH)D - 24,25(OH) D - and 1,25(OH) D fractions.
  
  
  RESULTS
  The PIs impair hepatocyte 25(OH)D - and macrophage 1,25(OH) D synthesis in a reversible, dose-dependent manner. Furthermore, PIs inhibit 1,25(OH) D -degradation in macrophages with lower potency than that elicited on 1alpha-hydroxylase. Thus, reduced macrophage 1,25(OH) D production is the net effect of PIs action.
  
  
  CONCLUSIONS
  In intact cells, HIV-PIs markedly suppress the activities of 25- and 1alpha-hydroxylase, which are critical in 1,25(OH) D synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH) D catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH) D homeostasis, defective 1,25(OH) D production could contribute to the bone demineralization in HIV patients.
authors.affiliation: Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Cozzolino
authors.forename: Marcos
authors.initials: M
authors.lastname: Vidal
authors.forename: Maria Vittoria
authors.initials: MV
authors.lastname: Arcidiacono
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.forename: Adriana S
authors.initials: AS
authors.lastname: Dusso
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D016723:Bone Remodeling; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003864:Depression, Chemical; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D019888:Nelfinavir / Q000494:pharmacology; D019438:Ritonavir / Q000494:pharmacology; D013250:Steroid Hydroxylases / Q000378:metabolism; D014807:Vitamin D / Q000378:metabolism*; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D017320:HIV Protease Inhibitors; D014807:Vitamin D; D019469:Indinavir; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D019888:Nelfinavir; D019438:Ritonavir