S-(2-hydroxy-3,4-epoxybutyl)glutathione

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: S-(2-hydroxy-3,4-epoxybutyl)glutathione
• 英文别名: S-(2-hydroxy-3,4-epoxybutyl)GSH；(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-[2-hydroxy-2-(oxiran-2-yl)ethyl]sulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
• 化学式: C₁₄H₂₃N₃O₈S
• 分子量: 393.418
• InChiKey: UHMJUFQJZLEVBD-DKEVHCRPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -5.1
• 重原子数：
  26
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  217
• 氢给体数：
  6
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  S-(2-hydroxy-3,4-epoxybutyl)glutathione 、 2'-脱氧腺苷 反应 12.0h， 生成 N5-((2R)-1-((carboxymethyl)amino)-3-((2,3-dihydroxy-4-((9-((2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-9H-purin-6-yl)amino)butyl)thio)-1-oxopropan-2-yl)-L-glutamine
  参考文献：
  名称：

  Conjugation of Butadiene Diepoxide with Glutathione Yields DNA Adducts in Vitro and in Vivo

  摘要：

  1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA-DNA and DNA-protein cross-links. We previously reported that DEB forms a conjugate with glutathione (GSH) and that the conjugate is considerably more mutagenic than several other butadiene-derived epoxides, including DEB, in the base pair tester strain Salmonella typhimurium TA1535 [Cho et al. (2010) Chem. Res. Toxicol. 23, 1544-1546]. In the present study, we determined steady-state kinetic parameters of the conjugation of the three DEB stereoisomers-R,R, S,S, and meso (all formed by butadiene oxidation)-with GSH by six GSH transferases. Only small differences (<3-fold) were found in the catalytic efficiency of conjugate formation (k(cat)/K-m) with all three DEB stereoisomers and the six GSH transferases. The three stereochemical DEB-GSH conjugates had similar mutagenicity. Six DNA adducts (N-3-adenyl, N-6-adenyl, N-7-guanyl, N-1-guanyl, N-4-cytidyl, and N-3-thymidyl) were identified in the reactions of DEB-GSH conjugate with nucleosides and calf thymus DNA using LC-MS and UV and NMR spectroscopy. N-6-Adenyl and N-7-guanyl GSH adducts were identified and quantitated in vivo in the livers of mice and rats treated with DEB ip. These results indicate that such DNA adducts are formed from the DEB-GSH conjugate, are mutagenic regardless of sterochemistry, and are therefore expected to contribute to the carcinogenicity of DEB.

  DOI：

  10.1021/tx200471x
• 作为产物：
  描述：

  谷胱甘肽 、 双环氧化丁二烯 在 rat liver glutathione transferase 作用下， 反应 1.0h， 生成 S-(2-hydroxy-3,4-epoxybutyl)glutathione
  参考文献：
  名称：

  Mutagenicity of a Glutathione Conjugate of Butadiene Diepoxide

  摘要：

  The mutagenicity and carcinogenicity of the important commodity chemical 1,3-butadiene are attributed to the epoxide products. We confirmed our previous work showing that expression of rat glutathione (GSH) transferase 5-5 enhances the mutagenicity of butadiene diepoxide in Salmonella typhimurium TA 1535. A GSH butadiene diepoxide conjugate was isolated and fully characterized by mass spectrometry and nuclear magnetic resonance as S-(2-hydroxy-3,4-epoxybutyl)GSH. The conjugate had a t(1/2) of 2.6 h (pH 7.4, 37 degrees C) and was considerably more mutagenic than butadiene diepoxide or monoepoxide in S. typhimurium. We propose that the GSH conjugate may be a major species involved in butadiene genotoxicity, not a detoxication product.

  DOI：

  10.1021/tx100304f

文献信息

• Hepatic and pulmonary glutathione conjugation of 1,2:3,4-diepoxybutane in human, rat, and mouse in vitro
  作者：Pieter J. Boogaard、Susan C.-J. Sumner、Max J. Turner、James A. Bond

  DOI：10.1016/0300-483x(96)03460-9

  日期：1996.10

  1,3-Butadiene (BD) is a carcinogen in rats and mice. Previous in vitro studies showed that mouse liver microsomes formed 1,2-epoxy-3-butene (BMO) from BD and 1,2:3,4-diepoxybutane (BDE) from BMO at much higher rates than rat or human microsomes. Blood and tissue levels of BDE were significantly lower in rats than in mice following exposure to BD. Since mice are much more susceptible to cancer induced by BD than rats, these findings suggest a key role for BDE in BD-induced carcinogenicity. The aim of this study was to characterize the glutathione (GSH) conjugation of BDE by cytosol from human liver and mouse and rat liver and lung in vitro. BDE and radiolabeled GSH were incubated with cytosol. Conjugates were identified by C-13-NMR and FAB mass spectroscopy and quantitated by HPLC. The enzyme kinetics for the conjugation of BDE with GSH suggest that the higher BDE blood concentrations in mice compared with rats following inhalation exposure to BD are not due to differences in GSH conjugation of BDE.
• Mutagenicity of a Glutathione Conjugate of Butadiene Diepoxide
  作者：Sung-Hee Cho、Elisabeth M. Loecken、F. Peter Guengerich

  DOI：10.1021/tx100304f

  日期：2010.10.18

  The mutagenicity and carcinogenicity of the important commodity chemical 1,3-butadiene are attributed to the epoxide products. We confirmed our previous work showing that expression of rat glutathione (GSH) transferase 5-5 enhances the mutagenicity of butadiene diepoxide in Salmonella typhimurium TA 1535. A GSH butadiene diepoxide conjugate was isolated and fully characterized by mass spectrometry and nuclear magnetic resonance as S-(2-hydroxy-3,4-epoxybutyl)GSH. The conjugate had a t(1/2) of 2.6 h (pH 7.4, 37 degrees C) and was considerably more mutagenic than butadiene diepoxide or monoepoxide in S. typhimurium. We propose that the GSH conjugate may be a major species involved in butadiene genotoxicity, not a detoxication product.
• Conjugation of Butadiene Diepoxide with Glutathione Yields DNA Adducts in Vitro and in Vivo
  作者：Sung-Hee Cho、F. Peter Guengerich

  DOI：10.1021/tx200471x

  日期：2012.3.19

  1,2,3,4-Diepoxybutane (DEB) is reported to be the most potent mutagenic metabolite of 1,3-butadiene, an important industrial chemical and environmental pollutant. DEB is capable of inducing the formation of monoalkylated DNA adducts and DNA-DNA and DNA-protein cross-links. We previously reported that DEB forms a conjugate with glutathione (GSH) and that the conjugate is considerably more mutagenic than several other butadiene-derived epoxides, including DEB, in the base pair tester strain Salmonella typhimurium TA1535 [Cho et al. (2010) Chem. Res. Toxicol. 23, 1544-1546]. In the present study, we determined steady-state kinetic parameters of the conjugation of the three DEB stereoisomers-R,R, S,S, and meso (all formed by butadiene oxidation)-with GSH by six GSH transferases. Only small differences (<3-fold) were found in the catalytic efficiency of conjugate formation (k(cat)/K-m) with all three DEB stereoisomers and the six GSH transferases. The three stereochemical DEB-GSH conjugates had similar mutagenicity. Six DNA adducts (N-3-adenyl, N-6-adenyl, N-7-guanyl, N-1-guanyl, N-4-cytidyl, and N-3-thymidyl) were identified in the reactions of DEB-GSH conjugate with nucleosides and calf thymus DNA using LC-MS and UV and NMR spectroscopy. N-6-Adenyl and N-7-guanyl GSH adducts were identified and quantitated in vivo in the livers of mice and rats treated with DEB ip. These results indicate that such DNA adducts are formed from the DEB-GSH conjugate, are mutagenic regardless of sterochemistry, and are therefore expected to contribute to the carcinogenicity of DEB.