Disease relevance of 8-Dehydrocholesterol

• Identification of 8-dehydrocholesterol (cholesta-5,8-dien-3 beta-ol) in patients with Smith-Lemli-Opitz syndrome [1].
• The ratio of 8-dehydrocholesterol to 7-dehydrocholesterol is higher in human SLO than in the animal disease model [2].

High impact information on 8-Dehydrocholesterol

• Silver ion high pressure liquid chromatography provides unprecedented separation of sterols: application to the enzymatic formation of cholesta-5,8-dien-3 beta-ol [3].
• Gas chromatography-mass spectrometry analysis revealed markedly elevated levels of 8-dehydrocholesterol and of cholest-8(9)-en-3beta-ol and helped to identify somatic mosaicism in a clinically unaffected man [4].
• In contrast to caput epididymidis, 7- and 8-dehydrocholesterol were barely detected in cauda epididymidis or testis [5].
• Smith-Lemli-Opitz syndrome (SLOS) is a hereditary disorder in which a defective gene encoding 7-dehydrocholesterol reductase causes the accumulation of noncholesterol sterols, such as 7- and 8-dehydrocholesterol [6].
• Here, we report high concentrations of 7- and 8-dehydrocholesterol in caput epididymidis and spermatozoa derived from caput epididymidis of Sprague-Dawley and Wistar rats, which comprised up to 30% of total sterols [5].

Anatomical context of 8-Dehydrocholesterol

• Sterol analysis from ocular tissues of an aborted fetus with SLOS showed increased 7- and 8-dehydrocholesterol and a low cholesterol concentration in the retinal pigment epithelium, lens, cornea, and sclera [7].
• However, the levels of 8(9)-cholestenol and 8-dehydrocholesterol were mildly increased in plasma, which was confirmed in cultured fibroblasts [8].

Associations of 8-Dehydrocholesterol with other chemical compounds

• Because the disposition of 7DHC and 8-dehydrocholesterol [8DHC; cholesta-5,8(9)-dien-3beta-ol] produced in this syndrome is little understood, we have analyzed urine from three young infants by gas chromatography/mass spectrometry to characterize its steroid metabolites [9].

Gene context of 8-Dehydrocholesterol

• The syndrome is caused by a block in cholesterol biosynthesis at the level of 7-dehydrocholesterol reductase (7-DHCR), which results in elevated levels of the cholesterol precursor 7-dehydrocholesterol (7-DHC) and its isomer 8-dehydrocholesterol (8-DHC) [10].
• Because CDPX2 patients have abnormal 8-dehydrosterol metabolism caused by mutations in 3beta-hydroxysteroid-delta8,delta7-isomerase, we measured plasma sterols in a patient with CHILD syndrome and found levels of 8-dehydrocholesterol and 8(9)-cholestenol increased to the same degree as in CDPX2 patients [11].
• We now show that the cholesterol concentration in CSF of Smith-Lemli-Opitz patients is markedly decreased and that 7- and 8-dehydrocholesterol concentrations are highly increased in comparison to controls [12].

Analytical, diagnostic and therapeutic context of 8-Dehydrocholesterol

• The aberrant sterols in the treated rats are similar to those detected in human SLO patients by gas chromatography coupled to mass spectrometry (1, 3, 4) and were identified as 7- and 8-dehydrocholesterol, two trienols (I and II), and 19-nor-5,7,9(10)-cholestatrien-3 beta-ol [2].

References