On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO.
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.
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Ingemar
I
Björkhem
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Ulf
U
Diczfalusy
Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Anita
A
Lövgren-Sandblom
Sachs' Children's Hospital, Karolinska Institutet, Stockholm, Sweden.
Lena
L
Starck
Östersund Hospital, Östersund, Sweden.
Monica
M
Jonsson
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN.
Keri
K
Tallman
Department of Clinical Medicine, Faculty of Health Science, University of Tromsö and Division of Cardiothoracic and Respiratory Medicine, University Hospital North Norway, Tromsö, Norway.
Henrik
H
Schirmer
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Lilian Bomme
LB
Ousager
Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea, UK.
Peter J
PJ
Crick
Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea, UK.
Yuqin
Y
Wang
Institute of Mass Spectrometry, College of Medicine, Swansea University, Singleton Park, Swansea, UK.
William J
WJ
Griffiths
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN.
F Peter
FP
Guengerich
D000293:Adolescent; D000328:Adult; D002648:Child; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D003684:Dehydrocholesterols / Q000097:blood*; D015536:Down-Regulation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007653:Ketocholesterols / Q000097:blood* / Q000235:genetics; D019082:Smith-Lemli-Opitz Syndrome / Q000097:blood* / Q000235:genetics / Q000473:pathology; D019294:Xanthomatosis, Cerebrotendinous / Q000097:blood* / Q000235:genetics / Q000473:pathology
D003684:Dehydrocholesterols; D007653:Ketocholesterols; C016705:7-dehydrocholesterol; C553219:CYP7A1 protein, human; D002790:Cholesterol 7-alpha-Hydroxylase; C003001:7-ketocholesterol
Smith-Lemli-Opitz syndrome; cerebrotendinous xanthomatosis; cholesterol 7,8-epoxide; cytochrome P-450 7A1; liquid chromatography-mass spectrometryn