Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patients with cerebrotendinous xanthomatosis

doi:10.1016/0009-8981(86)90192-0

Clinica Chimica Acta

Volume 160, Issue 3, 15 November 1986, Pages 255-263

https://doi.org/10.1016/0009-8981(86)90192-0 Get rights and content

Abstract

We studied the mitochondrial cytochrome P-450-linked monooxygenase system in livers of two patients with cerebrotendinous xanthomatosis (CTX). The three components of this system, which catalyzes steroid 27-hydroxylation, NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450_s27, were stained on a nitrocellulose sheet with antibodies against NADPH-adrenodoxin reductase, adrenodoxin, and cytochrome P-450_SCC, respectively, from bovine adrenocortical mitochondria. The concentrations of hepatoredoxin in the patients were not significantly different from a control, but the level of NADPH-hepatoredoxin reductase was three times that of the control. Cytochrome P-450_s27 was not detected in the patients, but it was present (22.8 pmol/mg of protein) in the control liver. This implies that a defect of mitochondrial cytochrome P-450_s27 prevents steroid 27-hydroxylation of hepatic mitochondria in patients with CTX.

References (24)

S Shefer et al.
Identification of pentahydroxy bile alcohols in cerebrotendinous xanthomatosis: characterization of 5β-cholestane-3α, 7α, 12α, 24ξ, 25-pentol and 5β-cholestane-3α, 7α, 12α, 23ξ, 25-pentol
J Lipid Res
(1975)
Y Atsuta et al.
On the stereospecificity of cholestanetriol 26-Monooxygenase
J Biol Chem
(1981)
Y Nakamura et al.
Requirement of a new flavoprotein and a non-heme iron-containing in the steroid 11β- and 18-hydroxylase system
Biochim Biophys Acta
(1966)
Y Ichikawa et al.
Isolation and properties of reduced nicotinamide adenine dinucleotide phosphate-hepatoredoxin reductase of rabbit liver mitochondria
Biochem Biophys Res Commun
(1977)
K Suhara et al.
Improved purification of bovine adrenal iron-sulfur protein
Biochim Biophys Acta
(1972)
Y Ichikawa et al.
The role of the sugar regions of components of the cytochrome P-450-linked mixed-function oxidase (monooxygenase) system of bovine adrenocortical mitochondria
Biochim Biophys Acta
(1982)
M Bradford
A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding
Anal Biochem
(1976)
K Suhara et al.
Bovine adrenal steroid hydroxylase system III. Reconstitution of adrenal iron-sulfur protein
Biochim Biophys Acta
(1974)
Y Ichikawa et al.
Characterization and reconstitution of components of the hepatic mitochondrial cytochrome P-450-linked mixed function oxidase
Y Ichikawa et al.
Tissue and subcellular distributions of cholecalciferol 25-hydroxylase: Cytochrome P-450_D25-linked monooxygenase system
Comp Biochem Phys
(1983)

K Saarem et al.

Subcellular localization of Vitamin D₃ 25-hydroxylase in human liver

J Biol Chem

(1984)

L Van Bogaert et al.

Une forme cérébrale de la cholesterinose généralisée

(1937)

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Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450s27 in livers of patients with cerebrotendinous xanthomatosis

Abstract

J Lipid Res

J Biol Chem

Biochim Biophys Acta

Biochem Biophys Res Commun

Biochim Biophys Acta

Biochim Biophys Acta

Anal Biochem

Biochim Biophys Acta

Comp Biochem Phys

J Biol Chem

Une forme cérébrale de la cholesterinose généralisée

Quantitative analysis of the mitochondrial cytochrome P-450-linked monooxygenase system: NADPH-hepatoredoxin reductase, hepatoredoxin, and cytochrome P-450_s27 in livers of patients with cerebrotendinous xanthomatosis