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2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV13-15 September 2000, Toronto, Canada |
PROTEASE INHIBITORS INHIBIT IN VITRO CONVERSION OF 25(OH)-VITAMIN D TO 1,25(OH)2-VITAMIN D
Antiviral Therapy 2000; 5(Suppl. 5):19 (abstract no. O30)
A Dusso, M Vidal, WG Powderly, KE Yarasheski and P Tebas
Washington University School of Medicine, St Louis, Mo., USA
BACKGROUND: Recently, we reported a high incidence of bone demineralization (in other words, osteopenia, osteoporosis) in people living with HIV/AIDS and treated with protease inhibitor (PI)- containing potent antiretroviral therapy. PIs are potent inhibitors of the hepatic cytochrome P450 enzyme system (especially CYP3A4 isoform). Two cytochrome P450 mixed-function oxygenases mediate vitamin D activation to its most potent circulating metabolite; 1,25(OH)2-vitamin D. Vitamin D-25-hydroxylase converts vitamin D to 25(OH)-vitamin D in the liver, which is activated to 1,25(OH)2-vitamin D by 25(OH)- vitamin D-1α-hydroxylase in the kidney. The formation of bioactive 1,25(OH)2-vitamin D by 1α-hydroxylase activity is mandatory for vitamin D control of calcium homeostasis.
OBJECTIVES: These studies examined whether indinavir, ritonavir or nelfinavir inhibit 1α-hydroxylase activity in vitro, and impair the conversion of 25(OH)-vitamin D to 1,25(OH)2- vitamin D.
DESIGN: Studies were conducted in the human monocyte-macrophage cell line THP-1, which expresses a 1α-hydroxylase identical to the renal enzyme responsible for the production of circulating 1,25(OH)2-vitamin D. THP-1 cells were incubated for 2 h in serum free RPMI-1640 containing 1% bovine serum albumin and vehicle or high-physiologic concentrations of ritonavir (11 µg/ml), indinavir (10 µM), or nelfinavir (6 µg/ml). The rate of conversion of tritiated-25(OH)-vitamin D3 to 1,25(OH)2-vitamin D3 by THP-1α-hydroxylase was measured after HPLC separation of both vitamin D metabolites.
RESULTS: All three PIs inhibited THP-l conversion of tritiated-25(OH)-vitamin D3 to 1,25(OH)2-vitamin D3. In this cell line, ritonavir inhibited the formation of the most active vitamin D metabolite by 80%, indinavir by 33%, and nelfinavir by 32% compared to vehicle treated controls.
CONCLUSIONS: In vivo, HIV-PIs inhibit cytochrome P450 enzyme activity. In vitro, HIV-PIs inhibited 1α-hydroxylase enzyme activity, which impairs bioactivation of vitamin D. Reduced formation of bioactive 1,25(OH)2-vitamin D may contribute to the bone demineralization associated with PI-containing potent antiretroviral therapy regimens in people living with HIV/AIDS.
000913
O30
Copyright © 2000 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.
