Disease relevance of C05502

• We propose that 22R-hydroxycholesterol offers a new means of neuroprotection against Abeta toxicity by inactivating the peptide [1].
• 22R-hydroxycholesterol was found to protect, in a dose-dependent manner, against Abeta-induced rat sympathetic nerve pheochromocytoma (PC12) and differentiated human Ntera2/D1 teratocarcinoma (NT2N) neuron cell death [1].
• Effect of 22R-hydroxycholesterol on the action of sphingomyelinase from Bacillus cereus toward bovine erythrocytes [2].

Psychiatry related information on C05502

• In Alzheimer's disease pathology neurosteroid biosynthesis is altered and a decrease in the intermediate 22R-hydroxycholesterol levels is observed [3].

High impact information on C05502

• These effects of 22R-hydroxycholesterol may provide a novel strategy to decrease amyloid beta secretion and consequently reduce the amyloid burden in the brain [4].
• Addition of the hydrosoluble cholesterol derivative, 22R-hydroxycholesterol, increased steroid production by the PBR-negative R2C cells, indicating that the cholesterol transport mechanism was impaired [5].
• However, no significant difference was observed in the steroidogenic ability of cells treated with 22R-hydroxycholesterol, which suggested a defect in cholesterol biosynthesis [6].
• These data suggest that 22R-hydroxycholesterol binds to Abeta and the formed 22R-hydroxycholesterol/Abeta complex is not toxic to rodent and human neurons [1].
• Furthermore, incubation of Leydig cells with 22R-hydroxycholesterol (5 microg/ml, 2 h), a cholesterol substrate derivative that does not need an assisted process to be delivered to the inner mitochondrial membrane, reversed most of the inhibitory effect of LIF on the steroid hormone formation [7].

Biological context of C05502

• The effect of 22R-hydroxycholesterol was found to be stereospecific because its enantiomer 22S-hydroxycholesterol failed to protect the neurons from Abeta-induced cell death [1].
• This occurs at a single active site and produces 22R-hydroxycholesterol and 22R-20 alpha-dihydroxycholesterol as intermediates [8].
• The relative hydroxylation rates of 20 alpha-hydroxycholesterol, 22R-hydroxycholesterol and 20 alpha,22R-dihydroxycholesterol indicate that all three hydroxylations catalysed by human cytochrome P-450scc occur at approximately the same rate [9].

Anatomical context of C05502

• Furthermore, incubation of Leydig cells with 22R-hydroxycholesterol (5 micrograms/ml, 2 h) reversed most of the inhibitory effect of TNF-alpha on androgen production [10].
• Such a moderate effect of the cytokine in the presence of 22R-hydroxycholesterol compared with that observed when androgen secretion was stimulated with the gonadotropin (up to 90% inhibition) indicate that TNF-alpha acts by dramatically reducing cholesterol substrate availability in the mitochondria [10].
• By using cultured porcine Leydig cells as a model, TNFalpha was shown to inhibit testosterone secretion when testicular cells were stimulated with hCG but not when incubated with 22R-hydroxycholesterol (a cholesterol substrate derivative that readily passes through cell and mitochondrial membranes) [11].
• Activators of the peroxisome proliferator-activated receptor (clofibrate or linoleic acid), farnesoid X-activated receptor (farnesol or juvenile hormone III), or liver X receptor (22R-hydroxycholesterol), were injected into the amniotic fluid of fetal rats on gestational day 17 [12].
• Both natural (22R-hydroxycholesterol/9-cis-retinoic acid) and synthetic (T0901317 and RO264456) LXR/RXR ligands increased ABCA1 and ABCG1 mRNAs in native macrophages and in cells loaded with acetylated LDL (acLDL) [13].

Associations of C05502 with other chemical compounds

• As expected, metabolism of 25-hydroxycholesterol by rat Leydig cells was much greater than cholesterol metabolism, as was metabolism of 20 alpha-hydroxycholesterol and 22R-hydroxycholesterol [14].
• Indeed, the TNF-alpha (20 ng/ml, 72 h) inhibitory effect on testosterone production was limited to about 20% (P less than 0.03) in Leydig cells supplied with 22R-hydroxycholesterol [10].
• The activity of the cholesterol side-chain cleavage enzyme was also unaffected by DMSO, as demonstrated by incubation of the cells with 22R-hydroxycholesterol [15].
• Inhibition by PP2 (0.3-10 microM) was also observed for the metabolism of 22R-hydroxycholesterol (22R-OHChol) to aldosterone in H295R cells [16].
• Measurement of the concentration of 20 alpha,22R-dihydroxycholesterol during incubation of placental mitochondria with 22R-hydroxycholesterol revealed that the lag in pregnenolone production was caused by accumulation of 20 alpha,22R-dihydroxycholesterol [9].

Gene context of C05502

• However, this stimulation was observed in cells when acutely (3 h) stimulated with hCG (0.01-1 ng/ml) but not when incubated with 22R-hydroxycholesterol (0.01-10 micrograms/ml) [17].
• TAT-STPHSTP behaved as a competitive PBR antagonist, which did not affect 22R-hydroxycholesterol-supported steroidogenesis [18].
• LH- or 22R -hydroxycholesterol-stimulated steroidogenesis in Leydig cells from immature rats did not decrease during the 24-h culture period, whereas ATP levels increased [19].
• The neuroprotective property of these compounds was coupled to their ability to displace radiolabeled 22R-hydroxycholesterol from Abeta, suggesting that the Abeta-22R-hydroxycholesterol physicochemical interaction contributes to their beneficial effect [20].
• Computational docking simulations of 22R-hydroxycholesterol and its derivatives on Abeta identified two binding sites [20].

Analytical, diagnostic and therapeutic context of C05502

• To investigate whether the chimeras bind substrate, titrations with 22R-hydroxycholesterol have been carried out [21].
• The intermediate obtained when 22R-hydroxycholesterol was used as the substrate was identified as 20R,22R-dihydroxycholesterol by HPLC, mass, and 1H-NMR spectroscopic analyses [22].

References