HIV-protease inhibitors impair vitamin D bioactivation to 1,25-dihydroxyvitamin D


    loading  Checking for direct PDF access through Ovid

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 D3 (1,25(OH)2D3), which is responsible for vitamin D3 actions in target tissues including bone. The 25- and 1α-hydroxylases regulate 1,25(OH)2D3 synthesis and 24-hydroxylase 1,25(OH)2D3 catabolism.Objective:To assess whether HIV-protease inhibitors (ritonavir, indinavir, nelfinavir) impair the activity of the main enzymes involved in 1,25(OH)2D3 homeostasis.Design and methods:Studies were conducted in the human hepatocyte (H3B)- and monocyte (THP-1) cell lines, expressing 25-hydroxylase and 1α-hydroxylase, respectively. The 24-hydroxylase expression was induced in macrophages by exposure to 1,25(OH)2D3. Conversion rates of vitamin D3 to 25-hydroxyvitamin D3 [25(OH)D3]; 25(OH)D3 to 1,25(OH)2D3 or 24,25(OH)2D3, and 1,25(OH)2D3 degradation were quantified in untreated and HIV-PI-treated cells after C18-cartridge extraction and high-performance liquid chromatography purification of 25(OH)D3- 24,25(OH)2D3- and 1,25(OH)2D3 fractions.Results:The PIs impair hepatocyte 25(OH)D3- and macrophage 1,25(OH)2D3 synthesis in a reversible, dose-dependent manner. Furthermore, PIs inhibit 1,25(OH)2D3-degradation in macrophages with lower potency than that elicited on 1α-hydroxylase. Thus, reduced macrophage 1,25(OH)2D3 production is the net effect of PIs action.Conclusions:In intact cells in vitro, HIV-PIs markedly suppress the activities of 25- and 1α-hydroxylase, which are critical in 1,25(OH)2D3 synthesis, while exerting mild inhibition of 24-hydroxylase, responsible for 1,25(OH)2D3 catabolism. If PIs elicit a similar potency in inhibiting these critical steps for 1,25(OH)2D3 homeostasis in vivo, defective 1,25(OH)2D3 production could contribute to the bone demineralization in HIV patients.

    loading  Loading Related Articles