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Atsushi Ichikawa - One of the best experts on this subject based on the ideXlab platform.
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Glycyrrhetinic Acid bound to 11β-hydroxysteriod dehydrogenase in rat liver microsomes
Biochimica et biophysica acta, 1992Co-Authors: Atsushi Irie, Tetsuya Fukui, Manabu Negishi, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract A binding protein which exibits high affinity to [ 3 H]Glycyrrhetinic-Acid in the rat liver microsomal fraction was solubilized with 0.2% Triton DF-18 and then purified to homogeneity. The equilibrium dissociation constant of the [ 3 H]Glycyrrhetinic-Acid binding reaction and the maximal concentration for the binding of the purified protein, as determined by Scatchard plot analysis, were 27.6 nM and 7.79 nmol/mg protein, respectively. The molecular mass of the subunit (34 kDa) and 30 amino Acids of N-terminal sequence of the purified protein were entirely the same as those of the reported 11β-hydroxysteriod dehydrogenase (11β-HSD). In each purification step, the recovery and purification (fold) of the Glycyrrhetinic-Acid binding activity corresponded to the values of 11β-HSD activity. These results show that the purified [ 3 H]Glycyrrhetinic-Acid binding protein is 11β-HSD. From the molecular mass of 11β-HSD (135 kDa) and the maximal concentration of the binding site, it was calculated that one Glycyrrhetinic Acid molecule binds to one 11β-HSD molecule. The inhibitory effects of various Glycyrrhetinic-Acid derivatives on [ 3 H]Glycyrrhetinic Acid binding and 11β-HSD activity indicate that the C 30 -carboxyl and C 11 -carbonyl groups of Glycyrrhetinic Acid are the principal structures for the 11β-HSD inhibition.
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Specific binding of Glycyrrhetinic Acid to the rat liver membrane.
Biochimica et biophysica acta, 1991Co-Authors: Manabu Negishi, Atsushi Irie, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract Glycyrrhetinic Acid bound specifically to a particulate fraction of rat liver. The binding was dependent on time, temperature and pH, equilibrium being reached after 10 min at 37°C. The equilibrium dissociation constant and the maximal concentration of the binding site, as determined by Scatchard plot analysis, were 31 nM and 43 pmol/mg protein, respectively, indicating a single binding site entity. The binding site was highly specific for Glycyrrhetinic Acid, glycyrrhizin, various steroids, various fatty Acids and retinoids showing no or only very low affinity. The binding was inhibited by boiling or treatment with trypsin or phospholipases. The specific activity of Glycyrrhetinic Acid binding was the highest in the liver, followed by in the kidney. The results suggest that Glycyrrhetinic Acid plays a significant role in the rat liver through its specific binding protein.
Sun Joo Lee - One of the best experts on this subject based on the ideXlab platform.
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18β-Glycyrrhetinic Acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity
Life Sciences, 2008Co-Authors: Chung Soo Lee, Yun Jeong Kim, Min Sung Lee, Eun Sook Han, Sun Joo LeeAbstract:Abstract Defects in mitochondrial function have been shown to participate in the induction of cell death in cancer cells. The present study was designed to assess the toxic effect of 18β-Glycyrrhetinic Acid against human cervix and uterus tumor cell line SiHa cells in relation to the mitochondria-mediated cell-death process and evaluate the combined toxic effect of 18β-Glycyrrhetinic Acid and anti-cancer drugs. 18β-Glycyrrhetinic Acid induced the nuclear damage, changes in the mitochondrial membrane permeability, formation of reactive oxygen species and depletion of glutathione in SiHa cells. It caused cell death by inducing the increase in the pro-apoptotic Bax protein and cytochrome c levels, reduction in anti-apoptotic Bcl-2 level, subsequent caspase-3 activation and loss of the mitochondrial transmembrane potential. Unlike 18β-Glycyrrhetinic Acid, a pro-compound glycyrrhizin up to 100 µM did not induce cell death and depletion of glutathione. Combined treatment of mitomycin c (or doxorubicin) and 18β-Glycyrrhetinic Acid revealed a synergistic toxic effect. Meanwhile, combination of camptothecin and 18β-Glycyrrhetinic Acid exhibited an additive cytotoxic effect. Results suggest that 18β-Glycyrrhetinic Acid may cause cell death in SiHa cells by inducing the mitochondrial membrane permeability change, leading to cytochrome c release and caspase-3 activation. The effect may be associated with increased formation of reactive oxygen species and depletion of glutathione. Combined treatment of antibiotic anti-cancer drug and 18β-Glycyrrhetinic Acid seems to exhibit a synergistic toxic effect.
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18beta-Glycyrrhetinic Acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity.
Life Sciences, 2008Co-Authors: Chung Soo Lee, Yun Jeong Kim, Min Sung Lee, Eun Sook Han, Sun Joo LeeAbstract:Defects in mitochondrial function have been shown to participate in the induction of cell death in cancer cells. The present study was designed to assess the toxic effect of 18beta-Glycyrrhetinic Acid against human cervix and uterus tumor cell line SiHa cells in relation to the mitochondria-mediated cell-death process and evaluate the combined toxic effect of 18beta-Glycyrrhetinic Acid and anti-cancer drugs. 18beta-Glycyrrhetinic Acid induced the nuclear damage, changes in the mitochondrial membrane permeability, formation of reactive oxygen species and depletion of glutathione in SiHa cells. It caused cell death by inducing the increase in the pro-apoptotic Bax protein and cytochrome c levels, reduction in anti-apoptotic Bcl-2 level, subsequent caspase-3 activation and loss of the mitochondrial transmembrane potential. Unlike 18beta-Glycyrrhetinic Acid, a pro-compound glycyrrhizin up to 100 microM did not induce cell death and depletion of glutathione. Combined treatment of mitomycin c (or doxorubicin) and 18beta-Glycyrrhetinic Acid revealed a synergistic toxic effect. Meanwhile, combination of camptothecin and 18beta-Glycyrrhetinic Acid exhibited an additive cytotoxic effect. Results suggest that 18beta-Glycyrrhetinic Acid may cause cell death in SiHa cells by inducing the mitochondrial membrane permeability change, leading to cytochrome c release and caspase-3 activation. The effect may be associated with increased formation of reactive oxygen species and depletion of glutathione. Combined treatment of antibiotic anti-cancer drug and 18beta-Glycyrrhetinic Acid seems to exhibit a synergistic toxic effect.
Zheng-xin Cao - One of the best experts on this subject based on the ideXlab platform.
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In-vitro metabolism of Glycyrrhetinic Acid by human and rat liver microsomes and its interactions with six CYP substrates.
The Journal of pharmacy and pharmacology, 2012Co-Authors: Kai Zhao, Ming Ding, Hui Cao, Zheng-xin CaoAbstract:Objectives Glycyrrhetinic Acid is the main metabolite of glycyrrhizin and the main active component of Licorice root. This study was designed to investigate the in-vitro metabolism of Glycyrrhetinic Acid by liver microsomes and to examine possible metabolic interactions that Glycyrrhetinic Acid may have with other cytochrome P450 (CYP) substrates. Methods Glycyrrhetinic Acid was incubated with rat liver microsomes (RLM) and human liver microsomes (HLM). Liquid chromatography tandem mass spectrometry was used for Glycyrrhetinic Acid or substrates identification and quantification. Key findings The Km and Vmax values for HLM are 33.41 µm and 2.23 nmol/mg protein/min, respectively; for RLM the Km and Vmax were 24.24 µm and 6.86 nmol/mg protein/min, respectively. CYP3A4 is likely to be the major enzyme responsible for Glycyrrhetinic Acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. Other human CYP isoforms have minimal or no activity toward Glycyrrhetinic Acid. The interactions of Glycyrrhetinic Acid and six CYP substrates, such as phenacetin, diclofenac, (S)-mephenytoin, dextromethorphan, chlorzoxazone and midazolam were also investigated. The inhibitory action of Glycyrrhetinic Acid was observed in CYP2C9 for 4-hydroxylation of diclofenac, CYP2C19 for 4′-hydroxylation of (S)-mephenytoin and CYP3A4 for 1′-hydroxylation of midazolam with half maximal inhibitory concentration (IC50) values of 4.3-fold, 3.8-fold and 9.6-fold higher than specific inhibitors in HLM, respectively. However, Glycyrrhetinic Acid showed relatively little inhibitory effect (IC50 > 400 µm) on phenacetin O-deethylation, dextromethorphan O-demethylation and chlorzoxazone 6-hydroxylation. Conclusions The study indicated that CYP3A4 is likely to be the major enzyme responsible for Glycyrrhetinic Acid metabolism in HLM while CYP2C9 and CYP2C19 are considerably less active. The results suggest that Glycyrrhetinic Acid has the potential to interact with a wide range of xenobiotics or endogenous chemicals that are CYP2C9, CYP2C19 and CYP3A4 substrates.
Nobuyuki Nagata - One of the best experts on this subject based on the ideXlab platform.
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Inhibition of rat acute inflammatory paw oedema by dihemiphthalate of Glycyrrhetinic Acid derivatives: comparison with Glycyrrhetinic Acid.
The Journal of pharmacy and pharmacology, 1993Co-Authors: Hideo Inoue, Nobuyuki Nagata, Kazuko Inoue, Tadao Takeuchi, Shoji ShibataAbstract:The anti-inflammatory profile of dihemiphthalate compounds of Glycyrrhetinic Acid derivatives in acute rat paw oedema induced by various vasoactive agents was compared with the parent compound. Three dihemiphthalate compounds (the di-sodium salt of 18 beta-olean-12-ene- 3 beta,30-diol di-O-hemiphthalate, 18 beta-olean-9(11),12-dione-3 beta,30-diol di-O-hemiphthalate and olean-11,13(18)-diene-3 beta,30-diol di-O-hemiphthalate), significantly inhibited development of carrageenan-induced rat paw oedema during the first 3 h (ED50 70, 90, and 108 mg kg-1 respectively, p.o.), while Glycyrrhetinic Acid (ED50, 200 mg kg-1) showed a significant inhibition of paw oedema 3 h after carrageenan treatment. The dihemiphthalate compounds also suppressed mouse paw oedema induced by histamine, bradykinin, and PAF acether at doses of less than 100 mg kg-1. However, these compounds failed to inhibit 5-HT-induced mouse paw oedema. Glycyrrhetinic Acid had little effect on mouse paw inflammation induced by the above irritants. The three compounds at 10(-7)-10(-4) M, inhibited histamine-induced contraction of guinea-pig isolated ileum. However, concentration-response curves to 5-HT and bradykinin were not affected by the same compounds. These results suggest that the dihemiphthalate compounds modulate vascular permeability caused by endogenous vasoactive agents as one of the anti-inflammatory mechanisms. This action is quite different from that of Glycyrrhetinic Acid.
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Glycyrrhetinic Acid bound to 11β-hydroxysteriod dehydrogenase in rat liver microsomes
Biochimica et biophysica acta, 1992Co-Authors: Atsushi Irie, Tetsuya Fukui, Manabu Negishi, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract A binding protein which exibits high affinity to [ 3 H]Glycyrrhetinic-Acid in the rat liver microsomal fraction was solubilized with 0.2% Triton DF-18 and then purified to homogeneity. The equilibrium dissociation constant of the [ 3 H]Glycyrrhetinic-Acid binding reaction and the maximal concentration for the binding of the purified protein, as determined by Scatchard plot analysis, were 27.6 nM and 7.79 nmol/mg protein, respectively. The molecular mass of the subunit (34 kDa) and 30 amino Acids of N-terminal sequence of the purified protein were entirely the same as those of the reported 11β-hydroxysteriod dehydrogenase (11β-HSD). In each purification step, the recovery and purification (fold) of the Glycyrrhetinic-Acid binding activity corresponded to the values of 11β-HSD activity. These results show that the purified [ 3 H]Glycyrrhetinic-Acid binding protein is 11β-HSD. From the molecular mass of 11β-HSD (135 kDa) and the maximal concentration of the binding site, it was calculated that one Glycyrrhetinic Acid molecule binds to one 11β-HSD molecule. The inhibitory effects of various Glycyrrhetinic-Acid derivatives on [ 3 H]Glycyrrhetinic Acid binding and 11β-HSD activity indicate that the C 30 -carboxyl and C 11 -carbonyl groups of Glycyrrhetinic Acid are the principal structures for the 11β-HSD inhibition.
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Specific binding of Glycyrrhetinic Acid to the rat liver membrane.
Biochimica et biophysica acta, 1991Co-Authors: Manabu Negishi, Atsushi Irie, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract Glycyrrhetinic Acid bound specifically to a particulate fraction of rat liver. The binding was dependent on time, temperature and pH, equilibrium being reached after 10 min at 37°C. The equilibrium dissociation constant and the maximal concentration of the binding site, as determined by Scatchard plot analysis, were 31 nM and 43 pmol/mg protein, respectively, indicating a single binding site entity. The binding site was highly specific for Glycyrrhetinic Acid, glycyrrhizin, various steroids, various fatty Acids and retinoids showing no or only very low affinity. The binding was inhibited by boiling or treatment with trypsin or phospholipases. The specific activity of Glycyrrhetinic Acid binding was the highest in the liver, followed by in the kidney. The results suggest that Glycyrrhetinic Acid plays a significant role in the rat liver through its specific binding protein.
Manabu Negishi - One of the best experts on this subject based on the ideXlab platform.
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Glycyrrhetinic Acid bound to 11β-hydroxysteriod dehydrogenase in rat liver microsomes
Biochimica et biophysica acta, 1992Co-Authors: Atsushi Irie, Tetsuya Fukui, Manabu Negishi, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract A binding protein which exibits high affinity to [ 3 H]Glycyrrhetinic-Acid in the rat liver microsomal fraction was solubilized with 0.2% Triton DF-18 and then purified to homogeneity. The equilibrium dissociation constant of the [ 3 H]Glycyrrhetinic-Acid binding reaction and the maximal concentration for the binding of the purified protein, as determined by Scatchard plot analysis, were 27.6 nM and 7.79 nmol/mg protein, respectively. The molecular mass of the subunit (34 kDa) and 30 amino Acids of N-terminal sequence of the purified protein were entirely the same as those of the reported 11β-hydroxysteriod dehydrogenase (11β-HSD). In each purification step, the recovery and purification (fold) of the Glycyrrhetinic-Acid binding activity corresponded to the values of 11β-HSD activity. These results show that the purified [ 3 H]Glycyrrhetinic-Acid binding protein is 11β-HSD. From the molecular mass of 11β-HSD (135 kDa) and the maximal concentration of the binding site, it was calculated that one Glycyrrhetinic Acid molecule binds to one 11β-HSD molecule. The inhibitory effects of various Glycyrrhetinic-Acid derivatives on [ 3 H]Glycyrrhetinic Acid binding and 11β-HSD activity indicate that the C 30 -carboxyl and C 11 -carbonyl groups of Glycyrrhetinic Acid are the principal structures for the 11β-HSD inhibition.
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Specific binding of Glycyrrhetinic Acid to the rat liver membrane.
Biochimica et biophysica acta, 1991Co-Authors: Manabu Negishi, Atsushi Irie, Nobuyuki Nagata, Atsushi IchikawaAbstract:Abstract Glycyrrhetinic Acid bound specifically to a particulate fraction of rat liver. The binding was dependent on time, temperature and pH, equilibrium being reached after 10 min at 37°C. The equilibrium dissociation constant and the maximal concentration of the binding site, as determined by Scatchard plot analysis, were 31 nM and 43 pmol/mg protein, respectively, indicating a single binding site entity. The binding site was highly specific for Glycyrrhetinic Acid, glycyrrhizin, various steroids, various fatty Acids and retinoids showing no or only very low affinity. The binding was inhibited by boiling or treatment with trypsin or phospholipases. The specific activity of Glycyrrhetinic Acid binding was the highest in the liver, followed by in the kidney. The results suggest that Glycyrrhetinic Acid plays a significant role in the rat liver through its specific binding protein.
