Oxidation of 5β-cholestane-3α,7α,12α-triol into 3α,7α,12α-trihydroxy-5β-cholestanoic acid by cytochrome P-45026 from rabbit liver mitochondria

Dahlbäck, Helena; Holmberg, Ingrid

doi:10.1016/0006-291x(90)92034-w

Cited by 23 publications

(5 citation statements)

References 22 publications

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“…Studies with purified CYP27A1 [28][29][30] and with cultured cells transfected with CYP27A1 cDNA [31] are consistent with one enzyme, i.e. CYP27A1, performing the complete oxidation of C 27 -alcohol into C 27 acid.…”

Section: Neutral or Classic Pathwaymentioning

confidence: 51%

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Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

168

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: Neutral or Classic Pathwaymentioning

confidence: 51%

“…CYP27A1 is able to introduce a 27-hydroxyl group in 24-hydroxycholesterol and 25-hydroxycholesterol [48] and to oxidize the 27-hydroxysterol into the corresponding C 27 acid [28][29][30]41].…”

Section: Cyp4a21 (Porcine Taurochenodeoxycholic Acid 6 -Hydroxylase)mentioning

confidence: 99%

Enzymes in the Conversion of Cholesterol into Bile Acids

Norlin¹,

Wikvall

2007

CMM

168

137

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“…The transformations in Scheme 1 are also analogous to those occurring during sterol side-chain modifications involved in bile acid synthesis (Bj6rkhem, 1985). Three systems have been proposed to account for this oxidative sequence (Dahlback and Holmberg, 1990): (i) according to the classical scheme (Dahlback and Holmberg, 1990), oxidation of 26-hydroxysteroid via the aldehyde to the acid is catalysed by the sequential actions of a cytosolic isoenzyme of alcohol dehydrogenase (Okuda and Okuda, 1983) and an NADI-dependent aldehyde dehydrogenase (Okuda et al, 1973); (ii) an NADI-dependent mitochondrial enzyme system from rabbit liver has been shown to catalyse the transformation of 26-hydroxysteroid to the acid; inhibition of 26-hydroxy group oxidation in both this and the cytosolic system (i), with the potent ethanol dehydrogenase inhibitor 4-heptylpyrazole, indicates that these two systems share some common properties (Dahlback et al, 1988); in this context, it is also relevant that superfamilies of aldehyde dehydrogenases, the members of which include non-specific cytosolic, mitochondrial and microsomal enzymes, have been recognized (Kedishvili et al, 1992;Johansson et al, 1988); (iii) interestingly, a mitochondrial cytochrome P-45026, which catalyses 26-hydroxylation during bile acid synthesis, has recently been shown to further transform the 26-hydroxysteroid into the corresponding acid; a mechanism has been proposed, involving a 26-aldehyde intermediate (Cali and Russell, 1991). This enzyme requires ferredoxin, ferredoxin reductase and NADPH for catalytic activity (Cali and Russell, 1991).…”

Section: Discussionmentioning

confidence: 99%

Induction of an inactivation pathway for ecdysteroids in larvae of the cotton leafworm, Spodoptera littoralis

Chen

Kabbouh

Fisher

et al. 1994

Biochemical Journal

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Treatment of the last-instar larvae of the cotton leafworm (Spodoptera littoralis) with ecdysteroids (moulting hormones) results in the induction of an ecdysteroid-inactivation pathway. Administration of ecdysone, 20-hydroxyecdysone or an ecdysteroid agonist, RH 5849, leads to induction of an ecdysteroid 26-hydroxylase activity. This induction occurred in both early sixth-instar larvae and in older larvae which had been headligated to prevent the normal developmental increase in ecdysone 20-mono-oxygenase activity. The induction of 26-hydroxylase activity requires both RNA and protein synthesis, as demonstrated by experiments involving actinomycin D and cycloheximide. The 26-aldehyde derivative of ecdysone and ecdyson-26-oic acid were also formed from ecdysone in the RH 5849-induced systems. Formation of the aldehyde and the corresponding 26-oic acid (ecdysonoic acid) from 26-hydroxyecdysone was directly demonstrated in a cell-free system, thus establishing the following inactivation pathway:

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“…Dahlbä ck and Holmberg (230) reported that incubation of 5␤-cholestane-3␣,7␣,12␣-triol with highly purified rabbit liver mitochondrial P-450 26 in the presence of ferredoxin, ferredoxin reductase, and NADPH gave two products, 5␤-cholestane-3␣,7␣,12␣,26-tetrol and 3␣,7␣,12␣-trihydroxy-5␤-cholestan-26-oic acid. The latter material was identified as follows.…”

Section: -Oxygenated Sterolsmentioning

confidence: 99%

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

Schroepfer

2000

Physiological Reviews

877

687

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Oxygenated derivatives of cholesterol (oxysterols) present a remarkably diverse profile of biological activities, including effects on sphingolipid metabolism, platelet aggregation, apoptosis, and protein prenylation. The most notable oxysterol activities center around the regulation of cholesterol homeostasis, which appears to be controlled in part by a complex series of interactions of oxysterol ligands with various receptors, such as the oxysterol binding protein, the cellular nucleic acid binding protein, the sterol regulatory element binding protein, the LXR nuclear orphan receptors, and the low-density lipoprotein receptor. Identification of the endogenous oxysterol ligands and elucidation of their enzymatic origins are topics of active investigation. Except for 24, 25-epoxysterols, most oxysterols arise from cholesterol by autoxidation or by specific microsomal or mitochondrial oxidations, usually involving cytochrome P-450 species. Oxysterols are variously metabolized to esters, bile acids, steroid hormones, cholesterol, or other sterols through pathways that may differ according to the type of cell and mode of experimentation (in vitro, in vivo, cell culture). Reliable measurements of oxysterol levels and activities are hampered by low physiological concentrations (approximately 0.01-0.1 microM plasma) relative to cholesterol (approximately 5,000 microM) and by the susceptibility of cholesterol to autoxidation, which produces artifactual oxysterols that may also have potent activities. Reports describing the occurrence and levels of oxysterols in plasma, low-density lipoproteins, various tissues, and food products include many unrealistic data resulting from inattention to autoxidation and to limitations of the analytical methodology. Because of the widespread lack of appreciation for the technical difficulties involved in oxysterol research, a rigorous evaluation of the chromatographic and spectroscopic methods used in the isolation, characterization, and quantitation of oxysterols has been included. This review comprises a detailed and critical assessment of current knowledge regarding the formation, occurrence, metabolism, regulatory properties, and other activities of oxysterols in mammalian systems.

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Oxidation of 5β-cholestane-3α,7α,12α-triol into 3α,7α,12α-trihydroxy-5β-cholestanoic acid by cytochrome P-45026 from rabbit liver mitochondria

Cited by 23 publications

References 22 publications

Enzymes in the Conversion of Cholesterol into Bile Acids

Enzymes in the Conversion of Cholesterol into Bile Acids

Induction of an inactivation pathway for ecdysteroids in larvae of the cotton leafworm, Spodoptera littoralis

Oxysterols: Modulators of Cholesterol Metabolism and Other Processes

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