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. DESIGN AND 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.
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. DESIGN AND 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: E M Stein; M T Yin; D J McMahon; A Shu; C A Zhang; D C Ferris; I Colon; J F Dobkin; S M Hammer; E Shane Journal: Osteoporos Int Date: 2010-06-29 Impact factor: 4.507
Authors: Pavel A Aronov; Laura M Hall; Katja Dettmer; Charles B Stephensen; Bruce D Hammock Journal: Anal Bioanal Chem Date: 2008-04-24 Impact factor: 4.142
Authors: Jennifer Jao; Laura Freimanis; Marisa M Mussi-Pinhata; Rachel A Cohen; Jacqueline P Monteiro; Maria L Cruz; Rhoda S Sperling; Andrea Branch; George K Siberry Journal: Int J Gynaecol Obstet Date: 2015-04-11 Impact factor: 3.561
Authors: Rene F Chun; Nancy Q Liu; T Lee; Joan I Schall; Michelle R Denburg; Richard M Rutstein; John S Adams; Babette S Zemel; Virginia A Stallings; Martin Hewison Journal: J Steroid Biochem Mol Biol Date: 2014-08-01 Impact factor: 4.292