Identification of proteasome gene regulation in a rat model for HIV protease inhibitor-induced hyperlipidemia.
Patients treated with highly active antiretroviral therapy may develop metabolic side effects such as hyperlipidemia, insulin resistance, lipoatrophy and lactic acidosis. The pathophysiology of these metabolic abnormalities is unknown, although some, e.g., lactic acidosis and lipoatrophy, are more associated with nucleoside use while protease inhibitors (PIs) have been shown to contribute to hyperlipidemia and insulin resistance. Identifying new PIs that are not associated with dyslipidemia has been hindered by the lack of mechanistic information and the unavailability of relevant animal models. In order to understand the molecular mechanism behind the hyperlipidemia associated with other protease inhibitors, and to develop a more effective, faster screen for compounds with this liability, we have analyzed expression profiles from PI-treated animals. Previously, we have shown that treatment of rats with ritonavir results in increases in the expression of proteasomal subunit genes in the liver. We show this increase is similar in rats treated with bortezomib, a proteasome inhibitor. In addition, we have treated rats with additional protease inhibitors, including atazanavir, which is associated with lower rates of lipid elevations in the clinic when administered in the absence of ritonavir. Our results indicate a strong correlation between proteasomal induction and lipid elevations, and have allowed us to develop a rapid screen for identifying novel PIs that do not induce the proteasome.
Waring
Jeffrey F
JF
Abbott Laboratories Global Pharmaceuticals Research and Development, 100 Abbott Park Rd, Abbott Park, IL 60064-6123, USA. jeff.waring@abbott.com
Ciurlionis
Rita
R
Marsh
Kennan
K
Klein
Larry L
LL
Degoey
David A
DA
Randolph
John T
JT
Spear
Brian
B
Kempf
Dale J
DJ
D000818:Animals; D000069446:Atazanavir Sulfate; D002219:Carbamates / Q000633:toxicity; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005663:Furans; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D017320:HIV Protease Inhibitors / Q000633:toxicity*; D006949:Hyperlipidemias / Q000139:chemically induced*; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000633:toxicity; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000633:toxicity; D013449:Sulfonamides / Q000633:toxicity
D002219:Carbamates; D005663:Furans; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D013449:Sulfonamides; D000069446:Atazanavir Sulfate; C095108:amprenavir; D046988:Proteasome Endopeptidase Complex; D019438:Ritonavir