Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis

S. Skrede, I. Bjorkhem, E. A. Kvittingen, M. S. Buchmann, S. O. Lie, C. East, Scott M Grundy

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Abstract

26-Hydroxylation of 5β-cholestane-3α,7α,12α-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were ~5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent K(m) was lowest for 5β-cholestane-3α,7α,12α-triol (1.3 μmol/liter) and highest for 5-cholestene-3β,7α-diol (12 μmol/liter). The rate of 26-hydroxylation was highest with 7α-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5β-cholestane-3α,7α,12α-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.

Original languageEnglish (US)
Pages (from-to)729-735
Number of pages7
JournalJournal of Clinical Investigation
Volume78
Issue number3
StatePublished - 1986

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Cerebrotendinous Xanthomatosis
Cholestanes
Cholestanetriol 26-Monooxygenase
Hydroxylation
Fibroblasts
Steroids
Skin
Liver
Carbon Monoxide

ASJC Scopus subject areas

  • Medicine(all)

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Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis. / Skrede, S.; Bjorkhem, I.; Kvittingen, E. A.; Buchmann, M. S.; Lie, S. O.; East, C.; Grundy, Scott M.

In: Journal of Clinical Investigation, Vol. 78, No. 3, 1986, p. 729-735.

Research output: Contribution to journalArticle

Skrede, S. ; Bjorkhem, I. ; Kvittingen, E. A. ; Buchmann, M. S. ; Lie, S. O. ; East, C. ; Grundy, Scott M. / Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis. In: Journal of Clinical Investigation. 1986 ; Vol. 78, No. 3. pp. 729-735.
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abstract = "26-Hydroxylation of 5β-cholestane-3α,7α,12α-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were ~5-10{\%} of those previously found in human liver homogenates, and were inhibited by CO. The apparent K(m) was lowest for 5β-cholestane-3α,7α,12α-triol (1.3 μmol/liter) and highest for 5-cholestene-3β,7α-diol (12 μmol/liter). The rate of 26-hydroxylation was highest with 7α-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5{\%} of healthy controls. No accumulation of endogenous 5β-cholestane-3α,7α,12α-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.",
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T1 - Demonstration of 26-hydroxylation of C27-steroids in human skin fibroblasts, and a deficiency of this activity in cerebrotendinous xanthomatosis

AU - Skrede, S.

AU - Bjorkhem, I.

AU - Kvittingen, E. A.

AU - Buchmann, M. S.

AU - Lie, S. O.

AU - East, C.

AU - Grundy, Scott M

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N2 - 26-Hydroxylation of 5β-cholestane-3α,7α,12α-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were ~5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent K(m) was lowest for 5β-cholestane-3α,7α,12α-triol (1.3 μmol/liter) and highest for 5-cholestene-3β,7α-diol (12 μmol/liter). The rate of 26-hydroxylation was highest with 7α-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5β-cholestane-3α,7α,12α-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.

AB - 26-Hydroxylation of 5β-cholestane-3α,7α,12α-triol and other C27-steroids was demonstrated in cultured skin fibroblasts from healthy individuals. Activities in skin fibroblasts were ~5-10% of those previously found in human liver homogenates, and were inhibited by CO. The apparent K(m) was lowest for 5β-cholestane-3α,7α,12α-triol (1.3 μmol/liter) and highest for 5-cholestene-3β,7α-diol (12 μmol/liter). The rate of 26-hydroxylation was highest with 7α-hydroxy-4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C27-steroid 26-hydroxylase. In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTX), 26-hydroxylation of C27-steroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5β-cholestane-3α,7α,12α-triol could be demonstrated in these cells, and the lowered formation of radioactive, 26-hydroxylated products could not be explained by dilution of the labeled exogenous substrate. The present results add strong evidence to the concept that the primary metabolic defect in CTX is a deficiency of C27-steroid 26-hydroxylase.

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