Role of the 26-hydroxylase in the biosynthesis of bile acids in the normal state and in cerebrotendinous xanthomatosis. An in vivo study.

Björkhem, Ingemar; Fausa, O; Hopen, G; Oftebro, H; Pedersen, Jan I.; Skrede, Sverre

doi:10.1172/jci110742

Cited by 63 publications

(23 citation statements)

References 23 publications

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“…Both enzymes appear to function optimally in the pH 7.5 range, as has been reported for other; vitamin D3 U'S012 Biochemistry: Hollis hydroxylases (32,41). Also, both subcellular la-hydroxylases in the present study were very sensitive to the presence of ketoconazole (Fig.…”

Section: Identificationsupporting

confidence: 85%

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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In vitro studies were performed to assess the ability of hepatic homogenates, mitochondria, and microsomes to la-hydroxylate 25-hydroxyvitamin D3 (25(OH)D3]. Addition of 25(OH)D3 to either hepatic mitochondria or microsomes caused a concentration-dependent increase in the production of 1,25-dihydroxyvitamin D3 [1,25(OH) Because of its inability to achieve substrate saturation, meaningful kinetic parameters could not be calculated for the hepatic microsomal la-hydroxylase. These data demonstrate the liver to be an even more dynamic organ than was previously believed with respect to vitamin D metabolism in that the liver has the potential to produce 1,25(OH)2D3 in situ by at least two separate mechanisms.It is well established that various side chain and/or A-ring hydroxylation reactions are essential for the metabolic activation of vitamin D3 (1, 2). Circulating vitamin D3 first undergoes a hepatic conversion to 25-hydroxyvitamin D3 [25(OH)D3] (3). The hydroxylase enzymes responsible for this conversion are known to be cytochrome P-450 mixed-function oxidases that are NADPH dependent and are located in both hepatic mitochondria (4-6) and microsomes (7,8). Final activation of 25(OH)D3 into 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] takes place primarily in the kidney (9). The renal enzyme responsible for this activation, 25(OH)D3 lahydroxylase, is also known to be a cytochrome P450 mixedfunction oxidase that is located solely in the inner mitochondrial membrane (10, 11). In recent years, other tissues have also been shown to be capable of synthesizing 1,25(OH)2D3, including placenta (12), bone cells (13), lymphatic tissue (14), and keratinocytes (15). Compared with the renal 25(OH)D3 la-hydroxylase, very little information is known with respect to the metabolic control of these extrarenal 25(OH)D3 lahydroxylases and essentially no information is available concerning their subcellular distribution.Because of the important role of 1,25(OH)2D3 in various aspects of hepatic function (16-24), the possibility that the liver could synthesize in situ this hormonal form of vitamin D3 was investigated. It is reported here that both hepatic mitochondria and microsomes possess a 25(OH)D3 lahydroxylase in significant amounts. These enzymes differ in some characteristics, but both appear to behave as cytochrome P-450 mixed-function oxidases. MN). Coomassie blue protein assay reagent was purchased from Pierce. Nicotinamide adenine dinucleotide phosphate, isocitrate, N,N'-diphenylethylenediamine (DPED), dithiothreitol, and ethylenediaminetetraacetic acid were purchased from Sigma. All solvents were of HPLC grade and were obtained from Fisher. MATERIALS AND METHODS ReagentsLivers. Livers from 3-month-old castrated male pigs, maintained on stock diet, were obtained at the time of slaughter. The livers were perfused with ice-cold 0.15 M NaCl, minced, and placed in an appropriate volume of ice-cold 50 mM Na2HPO4 (pH 7.4) buffer containing 0.25 M sucrose and 0.5 mM EDTA to provide a 20% (wt/vol) 6009The publication costs of th...

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Section: Identificationsupporting

confidence: 85%

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

Hollis

1990

Proc. Natl. Acad. Sci. U.S.A.

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“…We studied two Norwegian sisters with CTX (A.F., born 27 July 1941, and IJ., born 6 May 1935). Detailed records ofclinical findings and laboratory data have been published previously (5,6,12,13). Patient H.E.…”

Section: Methodsmentioning

confidence: 99%

“…5#-[2,2,3,_2H4]-7IB-3H-cholestane-3a,7a,12a-triol was synthesized as described previously (5). 7Il-3H-5IB-Cholestane3a,7a,12a-triol (9.9 mCi/mmol), 7#-3H-5ft-cholestane-3a,7a-diol (6.7 mCi/mmol), 7#%3H-5-cholestene-3,-7a-diol (158 mCi/mmol) and 4-4C-7a-hydroxy4-cholesten-3-one (1.3 mCi/mmol) were synthesized as described previously (5,6,13). All these compounds were purified by high performance liquid chromatography (HPLC) (see below) before use.…”

Section: Methodsmentioning

confidence: 99%

“…5#-cholestane-3a,7a,12a,26-tetrol, 5ft-cholestane3a,7a,26-triol, 7a,26-dihydroxy-4-cholesten-3-one and 5-cholestene-3(0,7a,26-triol were synthesized chemically or biosynthetically as described previously (5,6,15,16 The cells were grown and maintained as monolayers in tissue culture flasks (75 cm2) (Costar, Cambridge, MA) in MEM supplemented with 17% fetal calf serum. Penicillin (100 U/ml), streptomycin (100 ;g/ml), amphotericin (2 U/ml) and L-glutamine (1.5 ,mo1/ml) were added.…”

Section: Methodsmentioning

confidence: 99%

“…On the basis of our previous studies in vitro (5) and in vivo (6), we have proposed that the underlying defect is a deficiency of the mitochondrial C27-steroid 26-hydroxylase. Our findings are also consistent with the concept that the "26-hydroxylation pathway" is the major pathway for bile acid synthesis (7).…”

Section: Introductionmentioning

confidence: 99%

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

Skrede¹,

Björkhem²,

Kvittingen³

et al. 1986

J. Clin. Invest.

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100

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26-Hydroxylation of 5j6-cholestane-3a,7a,12a-triol and other C2rsteroids 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., was lowest for 5,B-cholestane3a,7a,12a-triol (1.3 Mmol/liter) and highest for 5-cholestene-3(3,7a-diol (12 Mmol/liter). The rate of 26-hydroxylation was highest with 7a-hydroxy4-cholesten-3-one. These characteristics are similar to those of hepatic mitochondrial C2rsteroid 26-hydroxylase.In skin fibroblasts from three patients with cerebrotendinous xanthomatosis (CTrX), 26-hydroxylation of C2rsteroids proceeded at a rate of only 0.2-2.5% of healthy controls. No accumulation of endogenous 5,B-cholestane-3a,7a,12a-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 Cr-steroid 26-hydroxylase.

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Unusual cerebrotendinous xanthomatosis with fronto‐temporal dementia phenotype

Guyant‐Maréchal

Verrips

Girard

et al. 2005

American J of Med Genetics Pt A

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Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP27). We report a 53-year-old man, with an unusual phenotype of CTX. He had xanthomas since adolescence. He had no mental retardation and developed at 44 years a progressive neuropsychiatric phenotype, suggestive of fronto-temporal dementia according to clinical Neary criteria. Cataract and ataxia were absent. Cerebral MRI revealed diffuse hyperintense T2 abnormalities in the supratentorial white matter without cerebellar atrophy or lesions, while Technetium-99m-ECD brain SPECT revealed a severe cerebellar hypoperfusion. Serum cholestanol level was elevated with excessive urinary bile alcohols excretion. Mutation analysis revealed that he was compound heterozygous for two mutations in the CYP27A1 gene: 1016 C > T (exon 5) on one allele and a novel mutation, 1435C > G (exon 8) on the other allele. A follow-up study was conducted to evaluate the effects of chenodeoxycholic acid (CDCA) and simvastatin treatment during 3 years. In spite of this treatment, cognitive functions declined but no other signs of neurological deterioration appeared.

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Role of the 26-hydroxylase in the biosynthesis of bile acids in the normal state and in cerebrotendinous xanthomatosis. An in vivo study.

Cited by 63 publications

References 23 publications

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

25-Hydroxyvitamin D3-1 alpha-hydroxylase in porcine hepatic tissue: subcellular localization to both mitochondria and microsomes.

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

Unusual cerebrotendinous xanthomatosis with fronto‐temporal dementia phenotype

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