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Gene expression profiling of rat liver reveals a mechanistic basis for ritonavir-induced hyperlipidemia.

Abstract：

:The molecular mechanisms of action of a HIV protease inhibitor, ritonavir, on hepatic function were explored on a genomic scale using microarrays comprising genes expressed in the liver of Sprague-Dawley rats (Rattus norvegicus). Analyses of hepatic transcriptional fingerprints led to the identification of several key cellular pathways affected by ritonavir treatment. These effects were compared to a compendium of gene expression responses for 52 unrelated compounds and to other protease inhibitors, including atazanavir and two experimental compounds. We identified genes involved in cholesterol and fatty acid biosynthesis, as well as genes involved in fatty acid and cholesterol breakdown, whose expressions were regulated in opposite manners by ritonavir and bezafibrate, a hypolipidemic agonist of the peroxisome proliferator-activated receptor alpha. Ritonavir also upregulated multiple proteasomal subunit transcripts as well as genes involved in ubiquitination, consistent with its known inhibitory effect on proteasomal activity. We also tested three other protease inhibitors in addition to ritonavir. Atazanavir did not impact ubiquitin or proteasomal gene expression, although the two other experimental protease inhibitors impacted both proteasomal gene expression and sterol regulatory element-binding protein-activated genes, similar to ritonavir. Identification of key metabolic pathways that are affected by ritonavir and other protease inhibitors will enable us to understand better the downstream effects of protease inhibitors, thus leading to better drug design and an effective method to mitigate the side effects of this important class of HIV therapeutics.

journal_name

Genomics

journal_title

Genomics

authors

Lum PY,He YD,Slatter JG,Waring JF,Zelinsky N,Cavet G,Dai X,Fong O,Gum R,Jin L,Adamson GE,Roberts CJ,Olsen DB,Hazuda DJ,Ulrich RG

doi

10.1016/j.ygeno.2007.06.004

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

464-73

issue

4

eissn

0888-7543

issn

1089-8646

pii

S0888-7543(07)00146-2

journal_volume

90

pub_type

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