Björkhem, Ingemar2; Diczfalusy, Ulf2; Lövgren-Sandblom, Anita2; Starck, Lena2; Jonsson, Monica2; Tallman, Keri2; Schirmer, Henrik2; Ousager, Lilian Bomme3; Crick, Peter J2; Wang, Yuqin2; Griffiths, William J2; Guengerich, F Peter2
1 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU2 unknown3 Human Genetics, Department of Clinical Research, Det Sundhedsvidenskabelige Fakultet, SDU
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. 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 have markedly upregulated 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 a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation 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.
Journal of Lipid Research, 2014, Vol 55, Issue 6, p. 1165-1172