New Aspects of Hexobarbital Metabolism: Stereoselective Metabolism, New Metabolic Pathway via GSH Conjugation, and 3‐Hydroxyhexobarbital Dehydrogenases

Takenoshita, Reiko; Toki, Satoshi

doi:10.1002/chin.200517280

Cited by 3 publications

(7 citation statements)

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“…Acetophenone (7) was transformed to 1-phenylethanol (10) at 9% yield (96% ee). In contrast, acetylpyrroles (8,9) were not reduced to alcohols (11,12) at all by rat liver S-9 fraction. Thus, isolation of the arylketone reductase was performed while monitoring the reduction of 4-acetylpyridine (1) to 1-(4-pyridyl)ethanol (4).…”

Section: Formation Of Secondary Alcohols From Aryl Ketones In Rat LIVcontrasting

confidence: 57%

“…Synthesis of 3-Acetylpyrrole (9) 3-Acetylpyrrole (9) was synthesized from 2-acetylpyrrole (8) in accordance with the reported method. 23 Syntheses of Authentic Samples of Reduced Aryl Ketones (4, 5, 6, 10, 11, and 12) Alcohols (4, 5, 6, 10, 11, and 12) were synthesized by reduction of the aryl ketones (1, 2, 3, 7, 8, or 9) with NaBH 4 (0.25 mol equivalent) followed by the purification by silica gel column chromatography.…”

Section: Instrumentsmentioning

confidence: 99%

“…The chirality of the secondary alcohol is very important because it affects their biological activity 7 and/or pharmacokinetics. 8 Thus, it is very interesting to investigate the stereoselectivity in the reduction reactions catalyzed by CBRs. However, such studies conducted to date have used mainly aldehydes, transformed to the achiral primary alcohols, as substrates.…”

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confidence: 99%

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Purification and characterization of rat liver enzyme catalyzing stereoselective reduction of acetylpyridines

et al. 2005

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Acetylpyridines (1-3) are known as aroma components of foods, perfumes, and smoking suppressants, showing several biological activities and constituting part of the structure of some important biologically active compounds. We purified and characterized an enzyme that catalyzes the stereoselective reduction of acetylpyridines so that we could clarify its function. The enzyme participating in the reductive metabolism of 4-acetylpyridine (1) in the rat liver was purified by successively applying ammonium sulfate fractionation, anion-exchange, gel filtration, and affinity chromatography, and it was definitively identified as 3alpha-HSD. It preferentially reduced acetylpyridines (1-3) and acetophenone (7) to their corresponding (S)-alcohols, with high enantioselectivity. Kinetic analyses of the compounds were performed, and the V(max)/K(m) values decreased in the order of 4-, 2-, and 3-acetylpyridine (1, 3, 2), while acetophenone (7) showed almost the same value as 3-acetylpyridine (2). These results suggested that the reduction of the substrates by 3alpha-HSD is affected by the nitrogen atom in the aromatic ring.

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Section: Formation Of Secondary Alcohols From Aryl Ketones In Rat LIVcontrasting

confidence: 57%

Section: Instrumentsmentioning

confidence: 99%

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confidence: 99%

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Purification and characterization of rat liver enzyme catalyzing stereoselective reduction of acetylpyridines

et al. 2005

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“…Interestingly, CYP2C19 in the present yeast cell expression system showed a substrate enantioselectivity of (R)-HB > (S)-HB, which is opposite to the reported selectivity [(R)-HB < (S)-HB] of rat 26 and human liver microsomal fractions. 10 Moreover, the recombinant CYP2C19 exerted the same metabolite diastereoselectivity (3 0 R < 3 0 S) for enantiomeric HB 3 0 -hydroxylation as that of the rat 27 and human liver microsomes.…”

Section: Discussioncontrasting

confidence: 83%

“…1). The research group of Toki, Fukuoka University, has been studying the metabolic fate of HB enantiomers (mainly HB oxidation and 3 0 -OH-HB dehydrogenation) in various experimental animal species for a long time (refer to the reviews of Takenoshita and Toki 26 and the references cited therein). Miyano et al 27 demonstrated that rat liver microsomes showed substrate enantioselectivity of (R)-HB < (S)-HB and metabolite diastereoselectivity of 3 0 R < 3 0 S in 3 0 -hydroxylation of HB enantiomers.…”

Section: Discussionmentioning

confidence: 99%

Stereoselective hexobarbital 3′‐hydroxylation by CYP2C19 expressed in yeast cells and the roles of amino acid residues at positions 300 and 476

et al. 2007

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We examined the enzymatic function of recombinant CYP2C19 in enantiomeric hexobarbital (HB) 3'-hydroxylation, and searched the roles of amino acid residues, such as Phe-100, Phe-114, Asp-293, Glu-300, and Phe-476 of CYP2C19 in the stereoselective HB 3'-hydroxylation, using a yeast cell expression system and site-directed mutagenesis method. CYP2C19 wild-type exerted substrate enantioselectivity of (R)-HB>>(S)-HB and metabolite diastereoselectivity of 3'(R)<3'(S) in 3'-hydroxylation of HB enantiomers. The substitution of Asp-293 by alanine failed to yield an observable peak at 450 nm in its reduced carbon monoxide-difference spectrum. CYP2C19-E300A and CYP2C19-E300V with alanine and valine, respectively, in place of Glu-300 exerted total HB 3'-hydroxylation activities of 45 and 108%, respectively, that of the wild-type. Interestingly, these two mutants showed substrate enantioselectivity of (R)-HB<(S)-HB, which is opposite to that of the wild-type, while metabolite diasteroselectivity remained unchanged. The replacement of Phe-476 by alanine increased total HB 3'-hydroxylation activity to approximately 3-fold that of the wild-type. Particularly, 3'(S)-OH-(S)-HB-forming activity elevated to 7-fold that of the wild-type, resulting in the reversal of the substrate enantioselectivity. In contrast, the substitution of phenylalanine at positions 100 and 114 by alanine did not produce a remarkable change in the total activity or the substrate enantioselectivity. These results indicate that Glu-300 and Phe-476 are important in stereoselective oxidation of HB enantiomers by CYP2C19.

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The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

Georgiou-Siafis,

Tsiftsoglou

2023

Antioxidants

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Glutathione (GSH) is a ubiquitous tripeptide that is biosynthesized in situ at high concentrations (1–5 mM) and involved in the regulation of cellular homeostasis via multiple mechanisms. The main known action of GSH is its antioxidant capacity, which aids in maintaining the redox cycle of cells. To this end, GSH peroxidases contribute to the scavenging of various forms of ROS and RNS. A generally underestimated mechanism of action of GSH is its direct nucleophilic interaction with electrophilic compounds yielding thioether GSH S-conjugates. Many compounds, including xenobiotics (such as NAPQI, simvastatin, cisplatin, and barbital) and intrinsic compounds (such as menadione, leukotrienes, prostaglandins, and dopamine), form covalent adducts with GSH leading mainly to their detoxification. In the present article, we wish to present the key role and significance of GSH in cellular redox biology. This includes an update on the formation of GSH-S conjugates or GSH adducts with emphasis given to the mechanism of reaction, the dependence on GST (GSH S-transferase), where this conjugation occurs in tissues, and its significance. The uncovering of the GSH adducts’ formation enhances our knowledge of the human metabolome. GSH–hematin adducts were recently shown to have been formed spontaneously in multiples isomers at hemolysates, leading to structural destabilization of the endogenous toxin, hematin (free heme), which is derived from the released hemoglobin. Moreover, hemin (the form of oxidized heme) has been found to act through the Kelch-like ECH associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor-2 (Nrf2) signaling pathway as an epigenetic modulator of GSH metabolism. Last but not least, the implications of the genetic defects in GSH metabolism, recorded in hemolytic syndromes, cancer and other pathologies, are presented and discussed under the framework of conceptualizing that GSH S-conjugates could be regarded as signatures of the cellular metabolism in the diseased state.

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New Aspects of Hexobarbital Metabolism: Stereoselective Metabolism, New Metabolic Pathway via GSH Conjugation, and 3‐Hydroxyhexobarbital Dehydrogenases

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 3 publications

References 1 publication

Purification and characterization of rat liver enzyme catalyzing stereoselective reduction of acetylpyridines

Purification and characterization of rat liver enzyme catalyzing stereoselective reduction of acetylpyridines

Stereoselective hexobarbital 3′‐hydroxylation by CYP2C19 expressed in yeast cells and the roles of amino acid residues at positions 300 and 476

The Key Role of GSH in Keeping the Redox Balance in Mammalian Cells: Mechanisms and Significance of GSH in Detoxification via Formation of Conjugates

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