7α‐Hydroxylation and 3‐Dehydrogenation Abolish the Ability of 25‐Hydroxycholesterol and 27‐Hydroxycholesterol to Induce Apoptosis in Thymocytes

Zhang, Jie; Xue, Yan; Jondal, Mikael; Sjövall, Jan

doi:10.1111/j.1432-1033.1997.00129.x

Cited by 26 publications

(27 citation statements)

References 42 publications

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“…As to structure-function relations, Zhang et al have reported that 7α-hydroxylation and 3-dehydrogenation abolish the ability of 25OHC and 27-hydroxycholesterol to induce apoptosis in thymocytes (37). For the present study we find that the sterols tested can cause apoptosis.…”

Section: Discussionsupporting

confidence: 57%

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

Johnson

Russell

Крылов

et al. 2000

Lipids

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Three oxidized analogs of cholesterol have been characterized for their ability to cause apoptotic cell death in CEM-C7-14 human leukemic cells. In addition to testing 15-ketocholestenol (K15), 15-ketocholestenol hydroxyethyl ether (CK15), and 7-ketocholesterol hydroxyethyl ether (CK7), an oxysterol of known apoptotic response, 25-hydroxycholesterol (25OHC), served as a standard for comparison. Growth studies based on dye exclusion by viable cells while using a sublethal concentration of oxysterols ranked their potency for cell kill as 25OHC > K15 > CK15 > CK7. Both the TUNEL assay (terminal deoxynucleotidyl transferase-mediated dUTP-X nick end labeling), which quantifies the amount of DNA nicks caused by a toxic agent, and the MTT assay, which measures cell metabolism and thus reflects cell viability, substantiated the same rank order. An ELISA assay for evaluating release of DNA fragments into the cytosol after treatment gave a similar potency order. The oncogene c-myc mRNA was suppressed by all three oxysterols, with 25OHC and K15 being the most potent suppressors. Hoechst and Annexin V staining documented that these oxysterols kill cells by an apoptotic pathway as evidenced by condensation of nuclear chromatin and plasma membrane inversion, respectively. From these in vitro studies, we believe that 25OHC, K15, and possibly CK15 have the potential to be chemotherapeutic agents.Paper no. L8259 in Lipids 35, 305-315 (March 2000).Both glucocorticoids and oxysterols can cause apoptosis of certain cells. For this action, glucocorticoids require a specific cytosolic protein, the glucocorticoid receptor (GR). No oxysterol receptor has been unequivocally identified, although two cellular proteins do specifically bind oxysterols: the oxysterol binding protein (OBP) and LXR, a member of the nuclear receptor family of proteins. As yet it is not certain that either protein is required for oxysterols' apoptotic actions. In our test system, the human leukemic cell line CEM, analysis of the events following addition of either class of steroid shows similarities at several points. These include a delay of about 1 d before the activation of caspases and nucleases, which occurs around the time of overt apoptosis. During this initial phase of cell death when the steroidal effects can be reversed, both types of steroids cause profound suppression of the oncogene product, cMyc (1,2). Because of their apoptotic action, glucocorticoids are used widely as antileukemic drugs. The similarity of effects of oxysterols suggests that they also might have therapeutic usefulness, alone, or in conjunction with glucocorticoids. Oxysterols are able to elicit changes in cholesterol synthesis, cell growth, and membrane composition, and can cause immunosuppression (3-8). These activities have led to many studies of oxysterols, usually as toxins in the environment and foods (9,10), or as implicated in atherosclerosis (11-14). The relatively greater sensitivity of certain malignant, as opposed to normal, cells offers an opportunity to use...

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Section: Discussionsupporting

confidence: 57%

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

Johnson

Russell

Крылов

et al. 2000

Lipids

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“…(17) There is some evidence for some OSstimulated DNA fragmentation in many cells i.e. endothelial cells, monocytes and macrophages, (58,59) smooth muscle cells, (60) lymphocytes (2,61) and thymocytes (62) (Table 4). Lizard et al (63) reported on the effects of various OS in causing apoptosis in bovine aortic endothelial cells.…”

Section: Oxycholesterols and Apoptosismentioning

confidence: 97%

Cellular toxicity of oxycholesterols

et al. 2006

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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.

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“…The first step in the metabolism of 27-hydroxycholesterol in the brain is likely to be catalyzed by the oxysterol 7 ␣ -hydroxylase (CYP7B1), which is present at surprisingly high levels in the brain (25). Because 7 ␣ -hydroxylated metabolites of oxysterols may be less cytotoxic and also less inhibitory in relation to cholesterol synthesis (26)(27)(28), the high levels of CYP7B1 in the brain may be regarded as a protective mechanism. These metabolites must, however, be removed from the brain.…”

Section: Discussionmentioning

confidence: 99%

Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

Heverin

Meaney

Lütjohann

et al. 2005

Journal of Lipid Research

233

228

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Side chain oxidized oxysterols have a unique ability to traverse lipophilic membranes. We tested the hypothesis that there is a net flux of 27-hydroxycholesterol from the circulation into the brain using plasma samples collected from the internal jugular vein and an artery of healthy male volunteers. Two independent studies were performed, one in which total levels of 27-hydroxycholesterol were measured and one in which the free fraction of 27-hydroxycholesterol was measured. In the majority of subjects studied, the level of 27-hydroxycholesterol was higher in the artery than in the vein, and uptake from the circulation was calculated to be about 5 mg/24 h. The distribution of 27-hydroxycholesterol in human brain was found to be consistent with an extracerebral origin, with a concentration gradient from the white to the gray matter-a situation opposite that of 24S-hydroxycholesterol, which is exclusively formed in brain. In view of the fact that the blood-brain barrier is impermeable to cholesterol and that 27-hydroxycholesterol is a potent regulator of several cholesterol-sensitive genes, the flux of 27-hydroxycholesterol into the brain may be an important link between intraand extracerebral cholesterol homeostasis.

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7α‐Hydroxylation and 3‐Dehydrogenation Abolish the Ability of 25‐Hydroxycholesterol and 27‐Hydroxycholesterol to Induce Apoptosis in Thymocytes

Cited by 26 publications

References 42 publications

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

Structure‐apoptotic potency evaluations of novel sterols using human leukemic cells

Cellular toxicity of oxycholesterols

Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain

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