Disease relevance of C01164

• Smith-Lemli-Opitz/RSH syndrome (SLOS), a relatively common birth-defect mental-retardation syndrome, is caused by mutations in DHCR7, whose product catalyzes an obligate step in cholesterol biosynthesis, the conversion of 7-dehydrocholesterol to cholesterol [1].
• None of the fabrics allowed the photoproduction of previtamin D3 from 7-dehydrocholesterol irradiated in vitro with up to 40 min of simulated sunlight or the elevation of serum vitamin D3 after irradiation with approximately one minimal erythema dose (MED) of UV-B in volunteers wearing jogging garments made of these fabrics [2].
• In separate experiments, human melanocytes and Cloudman S91 melanoma cells were repeatedly irradiated with physiologic doses of simulated sunlight and incubated between irradiations with provitamin D3, previtamin D3, vitamin D3, or 1,25-dihydroxyvitamin D3 [3].
• For the purpose of experimental teratology, an animal disease model consisting of the offspring of pregnant rats treated with AY 9944 or BM 15766, inhibitors of 7-dehydrocholesterol-delta 7-reductase, was established [4].
• 7-Dehydrocholesterol content was similar in epidermis from site-matched skin of fresh cadavers and white hemodialysis patients, 131 +/- 23 ng/mg versus 124 +/- 14 ng/mg skin, respectively [5].

High impact information on C01164

• The block may be sufficient to deprive an embryo or fetus of cholesterol and prevent normal development, whereas the incorporation of 7-dehydrocholesterol into all membranes may interfere with proper membrane function [6].
• The photosynthesis of previtamin D3 from 7-dehydrocholesterol in human skin was determined after exposure to narrow-band radiation or simulated solar radiation [7].
• A null mutation in the murine Dhcr7 causes an identical biochemical defect to that seen in SLOS, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol [1].
• Consistent with this finding, 7-dehydrocholesterol accelerates proteolysis of HMG-CoA reductase while sparing other key proteins [1].
• In distinction, the reduction of the double bond at C-7 [8] in 7-dehydrocholesterol to yield cholesterol catalyzed by 7-dehydrocholesterol-delta 7-reductase was nine times greater in controls than homozygotes microsomes (365 +/- 23 vs 40 +/- 4 pmol/mg protein per min, P < 0.0001) [8].

Chemical compound and disease context of C01164

• Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by reduced activity of 7-dehydrocholesterol (7DHC) reductase, resulting in a decreased level of cholesterol and increased concentrations of 7DHC and 8DHC in body fluids and tissues [9].
• Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol Delta(7)-reductase activity in chorionic villi [10].
• 7-Dehydrocholesterol, vitamin D2, and 24,25-(OH)2D3 did not stimulate hypercalcemia, hyperphosphatemia, or intestinal calcium uptake [11].
• The combination of low oestriol and sonographic findings suggested Smith Lemli Opitz syndrome (SLO), which was confirmed by a markedly increased amniotic fluid level of 7-dehydrocholesterol [12].

Biological context of C01164

• Accordingly, microsomal 7-dehydrocholesterol-delta 7-reductase is inherited abnormally in Smith-Lemli-Opitz homozygotes [8].
• Furthermore, the phenotype is rescued by application of 20-hydroxyecdysone or the precursor 7-dehydrocholesterol [13].
• Since 7-dehydrocholesterol is more rapidly oxidized than cholesterol, we hypothesized that 7-dehydrocholesterol enhances UVA-induced oxidative stress leading to keratinocyte death and inflammation [14].
• UVA induced 7-dehydrocholesterol concentration-dependent cell death at 24 h [14].
• Ketaconazole prevented the down-regulation of HMG-CoA reductase by 7-dehydrocholesterol, suggesting that an hydroxylated derivative of 7-dehydrocholesterol may be especially important in suppressing cholesterol synthesis [15].

Anatomical context of C01164

• Markedly inhibited 7-dehydrocholesterol-delta 7-reductase activity in liver microsomes from Smith-Lemli-Opitz homozygotes [8].
• Subcellular fractionation of human epidermal tissue revealed that most epidermal 7-dehydrocholesterol and previtamin D3 were in the membrane fraction, while only 20% were in the cytosol [16].
• Currently diagnosis relies on imaging, since SLOS is a malformation syndrome, and measurement of 7DHC levels in amniotic fluid and chorionic villus tissue [17].
• 7-Dehydrocholesterol enhances ultraviolet A-induced oxidative stress in keratinocytes: Roles of NADPH oxidase, mitochondria, and lipid rafts [18].
• Cultured skin fibroblasts from SLOS patients grown in fetal bovine serum or for 1 day in delipidated medium contain little 7-dehydrocholesterol (3 +/- 1% of total sterols) and HMG-CoA reductase activities are indistinguishable from that measured in control cells [15].

Associations of C01164 with other chemical compounds

• In Smith-Lemli-Opitz homozygotes, the transformation of 7-dehydrocholesterol to cholesterol by hepatic microsomes was blocked although 7-dehydrocholesterol was produced abundantly from lathosterol [8].
• The application of this methodology for the demonstration of the catalysis, by rat liver microsomes, of the conversion of 7-dehydrocholesterol to cholesta-5,8-dien-3 beta-ol is also presented [19].
• Tumor weights were 43% less (P < .05) than controls (5.9 +/- 1.5 g vs. 10.4 +/- 2.2 g) with sterol concentrations reduced 25%, and the precursor, 7-dehydrocholesterol, increased to represent 71% of the tumor sterols [20].
• To be certain that the cutaneous 24-dehydroprovitamin D3 was as susceptible as 7-dehydrocholesterol to ultraviolet photolysis, rat skin was exposed to ultraviolet radiation [21].
• Most humans depend on sun exposure to satisfy their requirements for vitamin D. Solar ultraviolet B photons are absorbed by 7-dehydrocholesterol in the skin, leading to its transformation to previtamin D3, which is rapidly converted to vitamin D3 [22].

Gene context of C01164

• In addition, we describe the metabolism of 7-dehydrocholesterol by CYP11A1 to a single product identified as 7-dehydropregnenolone [23].
• Like SCP2, recombinant SCPx also stimulates the microsomal conversion of 7-dehydrocholesterol to cholesterol and transfers phosphatidylcholine and 7-dehydrocholesterol from small unilamellar vesicles to acceptor membranes in vitro [24].
• Sterol C5 desaturase (SC5D) converts lathosterol to 7-dehydrocholesterol in cholesterol biosynthesis [25].
• The enzyme 7-dehydrocholesterol reductase (Dhcr7) catalyzes the reduction of 7-dehydrocholesterol (DHC), the terminal reaction of the pathway of cholesterol biosynthesis [26].
• The compound inhibited rat liver microsomal squalene synthase (IC50 = 1 nM) and 7-dehydrocholesterol (7DHC) reductase (IC50 = 1 microM; Lewis et al. 1995) [27].

Analytical, diagnostic and therapeutic context of C01164

• Comparison with results obtained by gas chromatography indicated that quantitation by TOF-SIMS yielded the sum of 7-dehydrocholesterol, isomeric dehydrocholesterol II, and sterol III, the latter two also being increased in the patients [28].
• This may be explained by a permanent block in 7-dehydrocholesterol-delta 7-reductase in SLO compared to a transient inhibition of this enzyme in the animal model [4].
• We describe a rapid and sensitive method involving time-of-flight secondary-ion mass spectrometry (TOF-SIMS) for specific laboratory diagnosis of the Smith-Lemli-Opitz syndrome, which is characterized by massive (approximately 1000-fold) accumulation of the biosynthetic cholesterol precursor 7-dehydrocholesterol [28].
• First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency) [29].
• It is concluded that chronic hemodialysis patients exhibit defective photoproduction of cholecalciferol, despite normal epidermal content of substrate, 7-dehydrocholesterol [5].

References