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On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO / William, Griffiths; Yuqin, Wang

The Journal of Lipid Research

Swansea University Authors: William, Griffiths, Yuqin, Wang

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DOI (Published version): 10.1194/jlr.P048603

Abstract

A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP) 7A1- catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product (Shinkyo R et al. J. Biol.Chem. 2011; 286:33021-33028). Some patients wit...

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Published in: The Journal of Lipid Research
Published: 2014
URI: https://cronfa.swan.ac.uk/Record/cronfa17919
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Abstract: A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP) 7A1- catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product (Shinkyo R et al. J. Biol.Chem. 2011; 286:33021-33028). Some patients with Cerebrotendinous Xanthomatosis (CTX) and all patients with Smith Lemli Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition the former patients havemarkedly up-regulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7-dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol as well as significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Down-regulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8-epoxide. Three patients with SLO were found to have markedly elevated levels of 7-ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7-ketocholesterol in SLO and some patients with CTX.
College: Swansea University Medical School