The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
Yorishige Imamura - One of the best experts on this subject based on the ideXlab platform.
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determination of absolute configuration of a metabolite hydroxyhexamide from Acetohexamide syntheses of and hydroxyhexamides and and acetoxyhexamides
ChemInform, 2010Co-Authors: Hiroyuki Akita, Masako Nozawa, Katsumi Kurashima, Shigeo Yamamura, Kenzi Seri, Yorishige ImamuraAbstract:Abstract Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with `Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave ( R )-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and ( S )- 6 (98% ee). Both ( S )- 6 and ( R )- 7 were individually converted to the ( S )-hydroxyhexamide 2 (>99% ee) and ( R )-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from Acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.
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Determination of Absolute Configuration of a Metabolite (-)-Hydroxyhexamide from Acetohexamide, Syntheses of (-)- and (+)-Hydroxyhexamides and (-)- and (+)-Acetoxyhexamides.
ChemInform, 2010Co-Authors: Hiroyuki Akita, Masako Nozawa, Katsumi Kurashima, Shigeo Yamamura, Kenzi Seri, Yorishige ImamuraAbstract:Abstract Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with `Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave ( R )-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and ( S )- 6 (98% ee). Both ( S )- 6 and ( R )- 7 were individually converted to the ( S )-hydroxyhexamide 2 (>99% ee) and ( R )-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from Acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.
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sex dependent pharmacokinetics of s hydroxyhexamide a pharmacologically active metabolite of Acetohexamide in rats
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Cadmium exposure decreases androgen-dependent metabolism of Acetohexamide in liver microsomes of male rats through its testicular toxicity
Archives of Toxicology, 2002Co-Authors: Hideaki Shimada, Shizuka Yamaguchi, Masaki Otagiri, Hideyuki Murata, Yorishige ImamuraAbstract:Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl_2) markedly decreased the activity of an enzyme (Acetohexamide reductase) catalysing the ketone-reduction of Acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of Acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on Acetohexamide reductase activity in liver cytosol of male rats.
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Sex-dependent pharmacokinetics of S(−)-hydroxyhexamide, a pharmacologically active metabolite of Acetohexamide, in rats
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
Masaki Otagiri - One of the best experts on this subject based on the ideXlab platform.
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sex dependent pharmacokinetics of s hydroxyhexamide a pharmacologically active metabolite of Acetohexamide in rats
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Cadmium exposure decreases androgen-dependent metabolism of Acetohexamide in liver microsomes of male rats through its testicular toxicity
Archives of Toxicology, 2002Co-Authors: Hideaki Shimada, Shizuka Yamaguchi, Masaki Otagiri, Hideyuki Murata, Yorishige ImamuraAbstract:Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl_2) markedly decreased the activity of an enzyme (Acetohexamide reductase) catalysing the ketone-reduction of Acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of Acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on Acetohexamide reductase activity in liver cytosol of male rats.
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Sex-dependent pharmacokinetics of S(−)-hydroxyhexamide, a pharmacologically active metabolite of Acetohexamide, in rats
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Hormonal regulation of male-specific 20β-hydroxysteroid dehydrogenase with carbonyl reductase-like activity present in kidney microsomes of rats
The Journal of steroid biochemistry and molecular biology, 2001Co-Authors: Yorishige Imamura, Hidenori Takada, Rika Kamizono, Masaki OtagiriAbstract:Progesterone, 17alpha-hydroxyprogesterone, cortisone and cortisol, which are C(21)-steroids with a ketone group at the 20-position, potently inhibited the activity of enzyme Acetohexamide reductase (AHR) responsible for the reductive metabolism of Acetohexamide in kidney microsomes of male rats. Furthermore, progesterone was a competitive inhibitor of AHR. In the case of progesterone usage as the substrate, 20beta-hydroxysteroid dehydrogenase (20beta-HSD) activity was much higher than 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) activity in kidney microsomes of male rats. These results indicate that AHR present in kidney microsomes of male rats, functions as 20beta-HSD with carbonyl reductase-like activity. In male rats, both testectomy and hypophysectomy decreased the renal microsomal 20beta-HSD activity, but the decreased enzyme activities were increased by the treatment with testosterone propionate (TP). We propose the possibility that TP treatment regulates the renal microsomal 20beta-HSD activity by acting directly on the kidney of male rats. This is supported from the fact that when TP was given to ovariectomized and hypophysectomized female rats, the male-specific 20beta-HSD activity was detected in their kidney microsomes.
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Catalytic properties for naphthoquinones and partial primary structure of rabbit heart Acetohexamide reductase.
Biological & pharmaceutical bulletin, 2000Co-Authors: Yorishige Imamura, Toshihisa Koga, Masaki Otagiri, Yukie Uriu, Kumiko Satoh, Akira HaraAbstract:The catalytic properties of rabbit heart Acetohexamide reductase (RHAR) for naphthoquinones were examined. RHAR efficiently reduced 1, 4-naphthoquinone and juglone (5-hydroxy-1, 4-naphthoquinone), whereas it had little or no ability to reduce menadione (2-methyl-1, 4-naphthoquinone) or plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone). The structural requirements for these four naphthoquinones and one Acetohexamide analog, and the kinetic mechanism for the inhibition of Acetohexamide reduction by juglone led us to conclude that the 2-methyl group of menadione and plumbagin prevents access of the substrates to the catalytic site of RHAR. Five of six peptides derived from RHAR showed 30-42% residue identities with regions in the amino acid sequence of mouse lung carbonyl reductase (MLCR) belonging to the short-chain dehydrogenase/reductase (SDR) family. The catalytically important residues (Arg-39, Ser-136, Tyr-149 and Lys-153) of MLCR were found in the peptide sequences of RHAR, despite the low residue identities between the two enzymes. RHAR is probably bast classified as a member of the SDR family similar to MLCR.
Hiroyuki Akita - One of the best experts on this subject based on the ideXlab platform.
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Determination of Absolute Configuration of a Metabolite (-)-Hydroxyhexamide from Acetohexamide, Syntheses of (-)- and (+)-Hydroxyhexamides and (-)- and (+)-Acetoxyhexamides.
ChemInform, 2010Co-Authors: Hiroyuki Akita, Masako Nozawa, Katsumi Kurashima, Shigeo Yamamura, Kenzi Seri, Yorishige ImamuraAbstract:Abstract Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with `Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave ( R )-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and ( S )- 6 (98% ee). Both ( S )- 6 and ( R )- 7 were individually converted to the ( S )-hydroxyhexamide 2 (>99% ee) and ( R )-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from Acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.
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determination of absolute configuration of a metabolite hydroxyhexamide from Acetohexamide syntheses of and hydroxyhexamides and and acetoxyhexamides
ChemInform, 2010Co-Authors: Hiroyuki Akita, Masako Nozawa, Katsumi Kurashima, Shigeo Yamamura, Kenzi Seri, Yorishige ImamuraAbstract:Abstract Enantioselective acetylation of (±)-4-(1-hydroxyethyl)benzenesulfonamide 6 with `Acylase I' (No. A 2156) from Aspergillus melleus in the presence of vinyl acetate gave ( R )-4-(1-acetoxyethyl)benzenesulfonamide 7 (98% ee) and ( S )- 6 (98% ee). Both ( S )- 6 and ( R )- 7 were individually converted to the ( S )-hydroxyhexamide 2 (>99% ee) and ( R )-hydroxyhexamide 2 (>99% ee), respectively. The absolute configuration of a metabolite (−)-hydroxyhexamide 2 from Acetohexamide 1 was found to be S based on unequivocal chemical methods including X-ray analysis.
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sex dependent pharmacokinetics of s hydroxyhexamide a pharmacologically active metabolite of Acetohexamide in rats
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Sex-dependent pharmacokinetics of S(−)-hydroxyhexamide, a pharmacologically active metabolite of Acetohexamide, in rats
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Hypoglycemic effect of S(−)-hydroxyhexamide, a major metabolite of Acetohexamide, and its enantiomer R(+)-hydroxyhexamide
Life sciences, 2001Co-Authors: Yorishige Imamura, Kazuko Sanai, Kenji Seri, Hiroyuki AkitaAbstract:A short-lasting hypoglycemic effect was observed when S(-)-hydroxyhexamide (S-HH), a major metabolite of Acetohexamide, and its enantiomer R(+)-hydroxyhexamide (R-HH), were administered orally to rats. Since the reductive metabolism of Acetohexamide is known to be reversible in rats, oral administration of R-HH may exhibit the hypoglycemic effect through the generation of Acetohexamide. However, oral administration of R-HH to rabbits, in spite of their inability to oxidize R-HH to Acetohexamide, caused a significant decrease and increase, respectively, of plasma glucose and insulin levels. Furthermore, both S-HH and R-HH were found to stimulate the secretion of insulin from hamster HIT T15 cells (pancreatic beta-cells). These results provide further evidence that both R-HH and S-HH exhibit a significant hypoglycemic effect.
Toshiyuki Higuchi - One of the best experts on this subject based on the ideXlab platform.
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INHIBITORY EFFECT OF DRUGS WITH A KETONE GROUP ON REDUCTION OF Acetohexamide CATALYZED BY CARBONYL REDUCTASE FROM RABBIT KIDNEY
Journal of enzyme inhibition, 1997Co-Authors: Yorishige Imamura, Toshihisa Koga, Toshiyuki Higuchi, Masaki Otagiri, E Sugino, Satoshi HibinoAbstract:The reduction of Acetohexamide catalyzed by carbonyl reductase from rabbit kidney was inhibited by befunolol, moperone, levobunolol, daunorubicin and loxoprofen, which have a ketone group within their chemical structures and are substrates for the enzyme. A significant correlation was observed between the common logarithm of Vmax/Km values of the enzyme for befunolol, moperone, levobunolol and daunorubicin and the percentage inhibition of the enzyme, confirming that these drugs are competitive substrates of the enzyme with respect to Acetohexamide. However, the plot for loxoprofen, a nonsteroidal anti-inflammatory drug with a ketone group, was apparently distant from the regression line obtained. Although nonsteroidal anti-inflammatory drugs with a ketone group such as suprofen and fenbufen were not reduced by the enzyme, they strongly inhibited the reduction of Acetohexamide catalyzed by the enzyme.
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Purification and Catalytic Properties of a Novel Acetohexamide-Reducing Enzyme from Rabbit Heart.
Journal of biochemistry, 1996Co-Authors: Yorishige Imamura, Toshihisa Koga, Masako Nozawa, Toshiyuki Higuchi, Masaki Otagiri, Akio Ryu, Hiroyuki AkitaAbstract:An enzyme catalyzing the metabolic reduction of Acetohexamide [4-acetyl-N-(cyclohexyl-carbamoyl)benzenesulfonamide], an oral antidiabetic drug, was purified to homogeneity from the cytosolic fraction of rabbit heart. The molecular mass of the purified enzyme was estimated to be 110 kDa by gel filtration and nondenaturing PAGE and 28 kDa by SDS-PAGE, suggesting that the enzyme is composed of four identical-size subunits. 4-Benzoyl-pyridine and p-nitroacetophenone, typical substrates of carbonyl reductase [EC 1.1.1.184], were not reduced by the enzyme. Of drugs with a ketone group tested, only Acetohexamide was a good substrate of the enzyme. the enzyme effectively reduced analogs substituted with various alkyl groups instead of the cyclohexyl group in Acetohexamide, although it had little or no ability to reduce analogs substituted with various alkyl groups instead of the methyl group in Acetohexamide. The enzyme was inhibited not only by quercetin, a well-known inhibitor of carbonyl reductase, but also by phenobarbital, a potent inhibitor of aldehyde reductase [EC 1.1.1.2]. These results indicate that the enzyme purified from rabbit heart is a novel enzyme responsible for the reduction of Acetohexamide and its analogs.
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Mechanism of Inhibition of Carbonyl Reductase from Rabbit Kidney by Phenylbutazone
Biological & pharmaceutical bulletin, 1995Co-Authors: Toshiyuki Higuchi, Yorishige Imamura, Masaki OtagiriAbstract:Phenylbutazone showed significant inhibition against the metabolic reduction of Acetohexamide catalyzed by carbonyl reductase purified from rabbit kidney. Thus, the inhibitory effect of phenylbutazone was kinetically examined. Phenylbutazone was a competitive inhibitor for the enzyme with respect to NADPH, whereas it noncompetitively inhibited the enzyme activity with respect to Acetohexamide. A fluorescence study revealed that phenylbutazone decreases the binding of NADPH to the free enzyme (apoenzyme). These results suggest that phenylbutazone causes the inhibition of carbonyl reductase by competing with NADPH in its coenzyme-binding domain.
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Stereoselective inhibition of carbonyl reductase from rabbit kidney by enantiomers of carprofen.
Iubmb Life, 1994Co-Authors: Toshiyuki Higuchi, Yorishige Imamura, Masaki OtagiriAbstract:The inhibitory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the reduction of Acetohexamide catalyzed by carbonyl reductase from rabbit kidney were examined. Of NSAIDs tested, only carprofen exhibited a pronounced stereoselectivity for the inhibition of the purified enzyme; (-)-carprofen inhibited more strongly the enzyme than three fold of its (+)-form. (-)-Carprofen was found to inhibit the enzyme noncompetitively with respect to Acetohexamide and competitively with respect to NADPH. Similar modes were observed for the inhibition of the enzyme by (+)-carprofen. The treatment of the apoenzyme with (-)-carprofen led to a time- and concentration-dependent loss of the catalytic activity. Furthermore, NADP+ afforded a significant protection against inactivation of the enzyme by (-)-carprofen. These results suggest that enantiomers of carprofen bind to coenzyme-binding domain of the enzyme and cause the stereoselective inhibition of Acetohexamide reduction by competing with NADPH.
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Catalytic Properties of Carbonyl Reductase from Rabbit Kidney for Acetohexamide and Its Analogs
Bioorganic Chemistry, 1994Co-Authors: Yorishige Imamura, Toshiyuki Higuchi, Masaki Otagiri, Shinji Nagumo, H. AkitaAbstract:Abstract Analogs submitted by ethyl, n-propyl, n-butyl, and isopropyl groups instead of methyl group adjacent to a ketone group of Acetohexamide were synthesized and the structural requirements of carbonyl reductase from rabbit kidney for these analogs were kinetically examined. The hydrophobicities in straight-chain alkyl groups of Acetohexamide analogs were found to play an important role in the catalytic activity and substrate-binding capacity of the enzyme. We propose the possibility that a hydrophobic pocket is located in the substrate-binding domain of the enzyme.
Hidenori Takada - One of the best experts on this subject based on the ideXlab platform.
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sex dependent pharmacokinetics of s hydroxyhexamide a pharmacologically active metabolite of Acetohexamide in rats
Comparative Biochemistry and Physiology C-toxicology & Pharmacology, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Sex-dependent pharmacokinetics of S(−)-hydroxyhexamide, a pharmacologically active metabolite of Acetohexamide, in rats
Comparative biochemistry and physiology. Toxicology & pharmacology : CBP, 2002Co-Authors: Yorishige Imamura, Masaki Otagiri, Miho Kaneko, Hidenori Takada, Hideaki Shimada, Hiroyuki AkitaAbstract:Abstract The pharmacokinetic profile of S (−)-hydroxyhexamide ( S -HH), a pharmacologically active metabolite of Acetohexamide, was examined in male and female rats. S -HH was eliminated more rapidly from plasma in the males than in the females. A significant sex difference was observed in the pharmacokinetic parameters of S -HH in rats. Testectomy caused significant alteration in these parameters of S -HH in male rats, whereas ovariectomy did not in the females. The co-administration of sulfamethazine significantly decreased the plasma clearance (CL p ) of S -HH in male rats, but had no effect in the females. The plasma concentrations of Acetohexamide generated from S -HH showed no sex-related difference. Furthermore, there was no difference in the accumulation of S -HH by renal cortical slices from male and female rats. We propose the possibility that the sex-dependent pharmacokinetics of S -HH in rats is mediated through the male-specific hydroxylation of the cyclohexyl ring catalyzed by a major cytochrome P450 (CYP) isoform (CYP2C11), although the detailed mechanism remains to be elucidated.
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Hormonal regulation of male-specific 20β-hydroxysteroid dehydrogenase with carbonyl reductase-like activity present in kidney microsomes of rats
The Journal of steroid biochemistry and molecular biology, 2001Co-Authors: Yorishige Imamura, Hidenori Takada, Rika Kamizono, Masaki OtagiriAbstract:Progesterone, 17alpha-hydroxyprogesterone, cortisone and cortisol, which are C(21)-steroids with a ketone group at the 20-position, potently inhibited the activity of enzyme Acetohexamide reductase (AHR) responsible for the reductive metabolism of Acetohexamide in kidney microsomes of male rats. Furthermore, progesterone was a competitive inhibitor of AHR. In the case of progesterone usage as the substrate, 20beta-hydroxysteroid dehydrogenase (20beta-HSD) activity was much higher than 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) activity in kidney microsomes of male rats. These results indicate that AHR present in kidney microsomes of male rats, functions as 20beta-HSD with carbonyl reductase-like activity. In male rats, both testectomy and hypophysectomy decreased the renal microsomal 20beta-HSD activity, but the decreased enzyme activities were increased by the treatment with testosterone propionate (TP). We propose the possibility that TP treatment regulates the renal microsomal 20beta-HSD activity by acting directly on the kidney of male rats. This is supported from the fact that when TP was given to ovariectomized and hypophysectomized female rats, the male-specific 20beta-HSD activity was detected in their kidney microsomes.
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20β-Hydroxysteroid Dehydrogenase Catalyzes Ketone-Reduction of Acetohexamide, an Oral Antidiabetic Drug, in Liver Microsomes of Adult Male Rats
The Journal of pharmacology and experimental therapeutics, 1998Co-Authors: Hidenori Takada, Masaki Otagiri, Yorishige ImamuraAbstract:We examined the catalytic properties and physiological function of an enzyme responsible for the ketone-reduction of Acetohexamide, an oral antidiabetic drug, in liver microsomes of adult male rats. Progesterone, 17α-hydroxyprogesterone, cortisone and cortisol, which have a ketone group at 20-position of C21-steroids, were potent inhibitors for ketone-reduction of Acetohexamide in liver microsomes of adult male rats. Progesterone was also found to inhibit competitively the ketone-reduction of Acetohexamide, suggesting that the ketone-reduction of Acetohexamide and progesterone is catalyzed by the same enzyme. When progesterone was used as a substrate, 20β-hydroxysteroid dehydrogenase present in liver microsomes of adult rats, such as Acetohexamide reductase, exhibited a male-specific and androgen-dependent activity. Furthermore, a significant correlation was observed between the activities of 20β-hydroxysteroid dehydrogenase and Acetohexamide reductase in liver microsomes of individual male rats at various ages. Based on all results, we conclude that 20β-hydroxysteroid dehydrogenase catalyzes the ketone-reduction of Acetohexamide in liver microsomes of adult male rats.
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Individual Variation of Acetohexamide Reductase Activities in Liver Microsomes and Cytosol of Rats
Biological & pharmaceutical bulletin, 1997Co-Authors: Yorishige Imamura, Yukiko Mori, Hidenori Takada, Yuri Kozono, Masaki OtagiriAbstract:We examined individual variations in Acetohexamide reductase activities in liver microsomes and cytosol of rats. Large differences among individuals were observed for Acetohexamide reductase activity in liver microsomes of male Fischer-344 (Fischer), Sprague-Dawley (SD) and Wistar rats at 9 weeks of age, except in the Wistar-Imamichi (Wistar-IM) strain. These four strains of female rats did not exhibit any microsomal enzyme activity. Although Acetohexamide reductase activities were fully detectable in liver cytosols from all the strains of male and female rats, there was neither strain-related difference nor considerable individual variation in the cytosolic enzyme activity. In liver microsomes of male Fischer rats at 4 weeks of age, Acetohexamide reductase activity was not detectable. The microsomal enzyme activity in male Fischer rats markedly increased at 6 weeks of age to approach the levels at 9 and 12 weeks of age, with large individual variations.
