Bile acid synthesis in man. In vivo activity of the 25-hydroxylation pathway.

Duane, William; Pooler, Pete A.; Hamilton, Jan Neal

doi:10.1172/jci113605

Cited by 35 publications

(20 citation statements)

References 16 publications

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“…This finding is in accordance with the concept that the 25-hydroxylase pathway is particularly important for cholic acid biosynthesis [45,46]. Honda et al [47] reported that murine It has been estimated that about 5% of total bile acids are formed by the 25-hydroxylase pathway in healthy humans [53]. However, when the 27-hydroxylase pathway for side chain oxidation is blocked, e.g.…”

Section: -Hydroxylase Pathwaysupporting

confidence: 86%

Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

166

137

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This article aims to give an overview on the characterization, properties and regulation of enzymes, particularly the cytochrome (CYP) P450 enzymes, in the formation of bile acids from cholesterol. Bile acids are biologically active molecules that promote absorption of dietary lipids in the intestine and stimulate biliary excretion of cholesterol. Bile acids and oxysterols, formed from cholesterol, act as ligands to nuclear receptors regulating the expression of important genes in cholesterol homeostasis. Thus, the bioactivation of cholesterol into bile acids is crucial for regulation of cholesterol homeostasis. The primary human bile acids, cholic acid and chenodeoxycholic acid, are formed from cholesterol via several pathways involving many different enzymes. Many of these enzymes are cytochrome P450 (CYP) enzymes, introducing a hydroxyl group in the molecule. The "classic" pathway of bile acid formation starts with a 7alpha-hydroxylation of cholesterol by CYP7A1 in the liver. The "acidic" pathway starts with a hepatic or extrahepatic 27-hydroxylation by CYP27A1. There also exist some quantitatively minor pathways which may be of importance under certain conditions. Formation of cholic acid requires insertion of a 12alpha-hydroxyl group performed by CYP8B1. Oxysterols are precursors to bile acids, participate in cholesterol transport and are known to affect the expression of several genes in cholesterol homeostasis. Enzymes with capacity to form and metabolize oxysterols are present in liver and extrahepatic tissues. The enzymes, nuclear receptors and transcription factors involved in bile acid biosynthesis are potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and to prevent atherosclerosis and other diseases related to disturbed cholesterol homeostasis. The review will also discuss some inborn errors of bile acid biosynthesis and the recently acquired knowledge on the genetic defects underlying these diseases.

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Section: -Hydroxylase Pathwaysupporting

confidence: 86%

Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

166

137

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“…Cholic acid is formed in these patients by a pathway involving 25-hydroxylated bile alcohols as intermediates. Under normal conditions this alternative pathway is of little or no importance, both in rats and man (21,22). Due to the reduced formation of bile acids, the negative feedback of the cholesterol 7␣-hydroxylase is reduced, resulting in an up-regulation of this enzyme.…”

mentioning

confidence: 99%

Markedly Reduced Bile Acid Synthesis but Maintained Levels of Cholesterol and Vitamin D Metabolites in Mice with Disrupted Sterol 27-Hydroxylase Gene

Rosen¹,

Reshef²,

Maeda³

et al. 1998

Journal of Biological Chemistry

237

170

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Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis.Mice with a disrupted cyp27 (cyp27 ؊/؊ ) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7␣-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7␣-hydroxylase and hydroxymethylglutaryl-CoA reductase (9-and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27 ؊/؊ mice only traces of bile alcohols were found, and there was no cholestanol accumulation.It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.

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“…A "25-hydroxylation pathway", initiating 25-hydroxylation of THC, is also believed to be involved in cholic acid biosynthesis in patients with CTX due to completely defective mitochondrial 26hydroxylase (2). The 25-hydroxylation pathway is thought to be an alternative pathway for cholic acid formation even in healthy individuals, since 5b-cholestane-3a,7a,12a,24,25-pentol is a normal constituent of urine from normal subjects and rats (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Urinary bile alcohol profile in infants with intrahepatic cholestasis: identification of 5ß-cholestane-3a,7a,24,25-tetrol

Nakagawa¹,

Une

Takenaka

et al. 1999

SPAE

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Urinary bile acids and bile alcohols were examined in six infants aged between 1 and 6 mo who had intrahepatic cholestasis. Following extraction, hydrolysis and solvolysis, cholanoids were analysed by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry. The relative ratio of the urinary excretion of bile alcohols to bile acids was very low (0.07-0.22) in three patients with mild to severe cholestasis, whereas the urinary excretion of bile alcohols was 2-4 times greater than that of the total bile acids in three patients with slight cholestasis. The urinary bile alcohol spectrum in infants appears to be quite different from that in adults. Although the major bile alcohol was 27-nor-5beta-cholestane-3alpha,7alpha,12alpha,24 ,25-pentol, comprising more than 50% of total urinary bile alcohols in healthy adults, it accounted for only 35% of total urinary bile alcohols in our patients. In addition, bile alcohols carrying chenodeoxycholic acid type nucleus were detected in our patients by comparison of the retention times and mass spectra with those of authentic standards. The presence of 5beta-cholestane-3alpha,7alpha,24,25-tetrol confirmed for the first time in this study may represent an alternative pathway for chenodeoxycholic acid biosynthesis via a "25-hydroxylation pathway" in early life.

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Bile acid synthesis in man. In vivo activity of the 25-hydroxylation pathway.

Cited by 35 publications

References 16 publications

Enzymes in the Conversion of Cholesterol into Bile Acids

Enzymes in the Conversion of Cholesterol into Bile Acids

Markedly Reduced Bile Acid Synthesis but Maintained Levels of Cholesterol and Vitamin D Metabolites in Mice with Disrupted Sterol 27-Hydroxylase Gene

Urinary bile alcohol profile in infants with intrahepatic cholestasis: identification of 5ß-cholestane-3a,7a,24,25-tetrol

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