title: Effects of antiretroviral treatment on paraoxonase 1 (PON1) activity in rats.
abstract: Highly active antiretroviral therapy (HAART), especially protease inhibitors (PIs), commonly used in HIV-infected patients, effectively suppresses a viral replication. However, it is frequently associated with significant side effects, including fat redistribution, lipodystrophy, hyperlipidemia, insulin resistance and diabetes mellitus. Currently, metabolic complications and atherosclerosis resulting from them become the major cause of mortality in HIV-infected patients receiving HAART. Paraoxonase 1 (PON1) is the HDL-bound esterase, which inhibits development of atherosclerosis by decomposing lipid peroxidation products and hydrolyzing homocysteine thiolactone. The aim of this study was to characterize the effects of HIV protease inhibitors on PON1 activity, total plasma homocysteine and protein-bound homocysteine thiolactone as well as lipid profile in rats. The study was performed on seven groups of male Wistar rats: (1) control; (2) and (3) receiving ritonavir (RTV) at doses of 10 and 50 mg/kg, respectively; (4) and (5) receiving atazanavir (ATV) at 10 and 100 mg/kg, respectively; (6) and (7) receiving saquinavir (SQV) at 10 and 50 mg/kg, respectively. All drugs were administered orally for 4 weeks. Compared to control animals, rats receiving PIs had significantly higher concentration of triglycerides and total cholesterol, but the levels of HDL-cholesterol were not different between groups. PON1 activity toward paraoxon was decreased in groups receiving PIs (control: 149 ± 5 U/ml; PIs-treated: RTV at doses 10 mg/kg 133 ± 9.5  U/ml, RTV at doses 50 mg/kg 134 ± 10.8 U/ml, SQV at doses 10 mg/kg 131 ± 9.2 U/ml, ATV at doses 10 mg/kg 132 ± 11.8 U/ml, ATV at doses 100 mg/kg 108 ± 7.8 U/ml). ATV reduced total homocysteine level around 25-28%, whereas other PIs had no effect on its concentration. In contrast, 10-15% increase in protein-bound homocysteine thiolactone was observed in PIs-receiving groups, such as RTV10, RTV50, SQV50, ATV10. In conclusion, dyslipidemia induced by PIs is associated with reduced PON1 activity as well as increased protein homocysteinylation. PON1 deficiency may contribute to increased risk of atherosclerosis in these patients.
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland. Electronic address: jola.racha@gmail.com.
authors.forename: Jolanta Elżbieta
authors.initials: JE
authors.lastname: Pastryk
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Rusek
authors.affiliation: Department of Pathophysiology, Medical University of Lublin, 8b Jaczewskiego Street, 20-090 Lublin, Poland.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Bełtowski
mesh_terms: D000818:Animals; D023241:Antiretroviral Therapy, Highly Active; D043303:Aryldialkylphosphatase / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D006710:Homocysteine / Q000378:metabolism; D008297:Male; D010261:Paraoxon / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D011480:Protease Inhibitors; D014280:Triglycerides; D006710:Homocysteine; D043303:Aryldialkylphosphatase; D010261:Paraoxon
keywords: Antiretroviral therapy; Atherosclerosis; Dyslipidemia; Paraoxonase; Protease inhibitors