The formation of cholest-5-ene-3β,26-diol as an intermediate in the conversion of cholesterol into bile acids by liver mitochondria

Mitropoulos, K. A.; Avery, Melissa D.; Myant, N. B.; Gibbons, Geoffrey F.

doi:10.1042/bj1300363

Cited by 39 publications

(10 citation statements)

References 12 publications

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“…An alternative explanation for changes in the relative proportions of cholic acid and chenodeoxycholic or ,-muricholic acids can be the existence of another pathway in the formation of bile acids, in addition to the major pathway involving initial 7a-hydroxylation of cholesterol [10,30], as has been suggested by several investigators to occur in the rat, hamster, rabbit and man [11][12][13][14][15]31]. This route may involve initial 26-hydroxylation of cholesterol by mitochondria, leading predominantly to the formation of chenodeoxycholic acid and /3-muricholic acid [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…This route may involve initial 26-hydroxylation of cholesterol by mitochondria, leading predominantly to the formation of chenodeoxycholic acid and /3-muricholic acid [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

“…Although the route starting with 7a-hydroxylation of cholesterol is considered to be quantitatively the most important one for formation of bile acids, alternative pathways can exist, particularly for the synthesis of chenodeoxycholic acid. This latter bile acid is preferentially synthesized from 26-hydroxycholesterol in the rat [11][12][13] and man [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

Princen¹,

Meijer

Wolthers

et al. 1991

Biochemical Journal

102

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Bile acid synthesis, determined by conversion of [4-14C]cholesterol into bile acids in rat and human hepatocytes and by measurement of mass production of bile acids in rat hepatocytes, was dose-dependently decreased by cyclosporin A, with 52 % (rat) and 45 % (human) inhibition at 10/,M. The decreased bile acid production in rat hepatocytes was due only to a fall in the synthesis of,-muricholic and chenodeoxycholic acids (-64 % at 10 4M-cyclosporin A), with no change in the formation of cholic acid. In isolated rat liver mitochondria, 26-hydroxylation of cholesterol was potently inhibited by the drug (concn. giving half-maximal inhibition = 4/tM). These results suggest that cyclosporin A blocks the alternative pathway in bile acid synthesis, which leads preferentially to the formation of chenodeoxycholic acid.

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Section: Discussionmentioning

confidence: 99%

“…This route may involve initial 26-hydroxylation of cholesterol by mitochondria, leading predominantly to the formation of chenodeoxycholic acid and /3-muricholic acid [11][12][13].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

Princen¹,

Meijer

Wolthers

et al. 1991

Biochemical Journal

102

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“…However, an alternative pathway may exist, specifically in the formation of chenodeoxycholic acid. Human and rat liver mitochondria are able to convert cholesterol into 27-hydroxycholesterol [2,3]. It has been shown that this intermediate can be further metabolized to 3,J-hydroxy-5-cholenoic acid in rat liver peroxisomes [4] and to 7a-hydroxy intermediates by human liver microsomes and mitochondria [5,6], ultimately leading to preferential formation of chenodeoxycholic acid in rat and man [7][8][9][10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes

Twisk¹,

Wit²,

Princen³

1995

Biochemical Journal

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In previous work we have demonstrated suppression of cholesterol 7 alpha-hydroxylase by bile acids at the level of mRNA and transcription, resulting in a similar decline in bile acid synthesis in cultured rat hepatocytes [Twisk, Lehmann and Princen (1993) Biochem. J. 290, 685-691]. In view of the substantial contribution of the 'alternative' or '27-hydroxylase' route to total bile acid synthesis, as demonstrated in cultured rat hepatocytes and in vivo in humans, we here evaluate the effects of various bile acids commonly found in bile of rats on the regulation of sterol 27-hydroxylase in cultured rat hepatocytes. Addition of taurocholic acid, the predominant bile acid in rat bile, to the culture medium of rat hepatocytes resulted in a 72% inhibition of sterol 27-hydroxylase activity. The effect was exerted at the level of sterol 27-hydroxylase mRNA, showing a time- and dose-dependent decline with a maximal suppression (-75%) at 50 microM taurocholic acid after 24 h of culture. The decline in mRNA followed first-order kinetics with an apparent half-life of 13 h. Under these conditions cholesterol 7 alpha-hydroxylase mRNA (-91%) and bile acid synthesis (i.e. chenodeoxycholic and beta-muricholic acid, -81%) were also maximally suppressed. In contrast, no change was found in the level of lithocholic acid 6 beta-hydroxylase mRNA. Assessment of the transcriptional activity of a number of genes involved in routing of cholesterol towards bile acids showed similar suppressive effects of taurocholate on expression of the sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase genes (-43% and -42% respectively), whereas expression of the lithocholic 6 beta-hydroxylase gene was not affected. Taurocholic acid and unconjugated cholic acid were equally as effective in suppressing sterol 27-hydroxylase mRNA. The more hydrophobic bile acids, chenodeoxycholic acid and deoxycholic acid, also produced a strong inhibition of 57% and 76% respectively, whereas the hydrophilic beta-muricholic acid was not active. We conclude that (1) a number of bile acids, at physiological concentrations, suppress sterol 27-hydroxylase by down-regulation of sterol 27-hydroxylase mRNA and transcriptional activity and (2) co-ordinated suppression of both sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase results in inhibition of bile acid synthesis in cultured rat hepatocytes.

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“…The presence of a unique electron transfer system involving a "cytochrome P-450"-like entity in liver mitochondria would be of profound physiological significance. Since C-25 hydroxylase system for the side chain of vitamin D, [32] and C-26 one for that of cholesterol [33] have also recently been reported in liver mitochondria, it seems probable that a similar mechanism is potentially functioning in liver mitochondria for other metabolites.…”

Section: Electron Transfer and Comparative Viewmentioning

confidence: 99%

Enzymatic Characteristics of CO‐Sensitive 26‐Hydroxylase System for 5β‐Cholestane‐3α, 7α, 12α‐triol in Rat‐Liver Mitochondria and Its Intramitochondrial Localization

Taniguchi

Hoshita

Okuda

1973

European Journal of Biochemistry

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The enzymatic characteristics of mitochondrial 26-hydroxylase system for 5f3-cholestane3a,7a,12a-triol were studied with rat liver mitochondria and the inner membrane-matrix fractions with special reference to its intramitochondrial localization.1. Conditions for the assay of enzymatic activity of the hydroxylase system were established with rat liver mitochondrial preparations and inner membrane-matrix fractions derived by digitonin treatment.2. It was established that rat liver mitochondria, as well as microsomes, possessed the hydroxylase system for 5p-cholestane-3a,7a, 12a-trio1 as an intrinsic constituent. Product analyses revealed that only the mitochondrial hydroxylase system was specifically active for C-26 position. I n contrast, the microsomal system was found to be apparently unspecific on C-26 position but rather more active for other adjacent positions. 3. Among the tested citric acid cycle intermediates and nicotinamide coenzymes, isocitrate and NADPH exerted the most remarkable enhancement of the 26-hydroxylase activity. NADP and NADH were totally inert under the present assay conditions. 4. Partial rupture of the mitochondrial structure by hypotonic or digitonin treatment was essential for the reactivity of 26-hydroxylase system under the present experimental conditions. Accessibility to the intramitochondrial reacting site of the exogenous reactants such as NADPH, isocitrate and 5f3-cholestane-3a,7a, l2a-trio1 in particular was apparently improved by the partial rupture.5. The NADPH-dependent or isocitrate-dependent 26-hydroxylase system was totally insensitive to inhibitors of the respiratory electron transfer such as potassium cyanide, antimycin A, rotenone and amytal. However, it was specifically inhibited by phenyl isocyanide.6. Remarkable sensitivity to carbon monoxide of the 26-hydroxylase system was demonstrated. Apparent Michaelis constant for oxygen and partition coefficient (between carbon monoxide and oxygen) of the 26-hydroxylase system were estimated to be approximately 10-20 pM and 0.1, respectively. Thus, the possible functioning of a "cytochrome P-450"-like entity in intramitochondrial 26-hydroxlase system was proposed.7. The localization of 26-hydroxylase system was assigned to be in the inner membranematrix region, on the basis of the distribution of intramitochondrial marker enzymes during the course of serial solubilization by digitonin.The metabolic system in hepatic cells for conversion of cholesterol to bile acid consists of multiple enzymatic steps. The characterization of each Enzymes. 58 -Cholestanc -3a,7a,12a -trio1 hydroxylasc (EC 1.9%1.-); 5,9-cholestane-3a,7a,l2a, 26-tetrol dehydrogenase (EC 1.1.1. -); 5~-cholestane-3a,7a,l2a-triol-26-a1 dehydrogenase (EC 1.2

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The formation of cholest-5-ene-3β,26-diol as an intermediate in the conversion of cholesterol into bile acids by liver mitochondria

Cited by 39 publications

References 12 publications

Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis

Suppression of sterol 27-hydroxylase mRNA and transcriptional activity by bile acids in cultured rat hepatocytes

Enzymatic Characteristics of CO‐Sensitive 26‐Hydroxylase System for 5β‐Cholestane‐3α, 7α, 12α‐triol in Rat‐Liver Mitochondria and Its Intramitochondrial Localization

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