Cellular toxicity of oxycholesterols

Abstract

Oxycholesterols (OS) are formed from cholesterol or its immediate precursors by enzymatic or free radical action in vivo, or they may be derived from food. OS exhibit a wide spectrum of biological activities. In OS cytotoxicity, several mechanisms seem to be involved: e.g. inhibition of HMG-CoA reductase activity, antiproliferative action, apoptosis induction, replacement of cholesterol by OS in membranes followed by changes in cellular membrane structure and functionality, and immune system functions alteration. Furthermore, OS may be mutagenic and carcinogenic and may serve as intracellular signaling or regulatory molecules. Here we review OS cellular activities with special attention to the cytotoxic action in vivo and in vitro using experimental models.

Cytotoxic oxysterols induce caspase-independent myelin figure formation and caspase-dependent polar lipid accumulation

“…Among the oxysterols considered (7KC,5 ,5 ,, and in agreement with previous investigations Wielkoszynski et al 2006), cytotoxic activities including increased permeability to PI, and morphological nuclear changes (cells with swollen nuclei considered as oncotic cells; cells with condensed and/or fragmented nuclei characteristic of apoptotic cells) (Majno and Joris 1995;Fink and Cookson 2005) were only observed with 7-KC, 7 -OH, and 5 ,6 -epoxide. Moreover, as myelin Wgures were only detected with these cytotoxic oxysterols, and as they were not found in treatments with the potent inducers of apoptosis or autophagy studied daunorubicin,tunicamycin,rapamycin), nor with cytosine -D-arabinofuranoside, vinblastine, cycloheximide, or staurosporine (MiguetAlfonsi et al 2002), our observations reinforce the hypothesis that multilamellar structures might constitute suitable markers of oxysterol-induced cell death.…”

Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis

“…Since it is well established that some oxysterols have detrimental biological activities (induction of cell death, pro-oxidative and pro-inflammatory activities) (Björkhem and Diczfaluzsy, 2002;Carpenter, 2002;Meynier et al, 2005;Van Reyk et al, 2006;Wielkoszynski et al, 2006), they can therefore contribute to the initiation and development of important diseases.…”

“…Since atherosclerosis is characterized early at the subendothelial level by an intracellular accumulation of lipids in macrophages and smooth muscle cells (Berliner and Heinecke, 1996), and given that these cells can transform into foam cells (Bobryshev, 2006), which are lipid-laden cells of the first step of atherosclerosis (Stary et al, 1995), it is important to specify the role played by some oxysterols in intracellular lipid accumulation, especially with oxysterols present at high levels in atherosclerotic plaques, which can induce cytotoxic effects from 7-ketocholesterol and 7b-hydroxycholesterol, for example (Brown and Jessup, 1999;Wielkoszynski et al, 2006). Death of macrophage foam cells leads to the development of the lipid core of advanced atherosclerotic lesions while the death of smooth muscle cells thins the fibrous cap.…”

Cholesterol oxidation in the retina: implications of 7KCh formation in chronic inflammation and age-related macular degeneration

“…This occurs readily in lipoprotein deposits and atherosclerotic plaques. The enzymatic pathways can form both B-ring and side-chain hydroxylated oxysterols depending on the enzyme and the tissue ( 5,7,(30)(31)(32) ( Fig. 1B ).…”