Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers.
Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers.
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DOI：
10.1016/s0021-9258(18)54551-8
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发表时间：
1991-11
期刊：
影响因子：
--
通讯作者：
C. A. Hinchman;H. Matsumoto;T. W. Simmons;N. Ballatori
中科院分区：
文献类型：
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作者：
C. A. Hinchman;H. Matsumoto;T. W. Simmons;N. Ballatori
由于大鼠中γ-谷氨酰转移酶的肝脏活性较低，因此通常认为肝脏在谷胱甘肽结合物的降解（巯基尿酸形成的限制步骤）中仅起次要作用。然而，最近的研究结果表明，肝脏在谷胱甘肽催化剂中具有突出的作用，特别是在大鼠以外的物种中。为了研究肝脏巯基尿酸生物合成的贡献，巯基尿酸形成进行了比较，在离体灌流的肝脏从大鼠和豚鼠给予0.3或3.0 μ mol的1-氯-2，4-二硝基苯（CDNB）。化学合成的谷胱甘肽结合物，巯基尿酸，和中间代谢产物的CDNB被用作标准的胆汁和灌注液样品的高效液相色谱分析。胆汁排泄几乎占所有回收的代谢产物。一个显着的种属差异，观察到的CDNB代谢的模式。给予0.3 μ mol CDNB的大鼠肝脏以谷胱甘肽结合物的形式排泄总胆汁代谢物的55%，以巯基尿酸的形式排泄8.2%，而豚鼠肝脏仅以谷胱甘肽结合物的形式排泄4.8%，以巯基尿酸的形式排泄47%。巯基形成也具有剂量依赖性，在0.3 μ mol与3.0 μ mol剂量下形成的比例较大（大鼠中为8.2%与3.7%;豚鼠中为47%与19%）。肝谷胱甘肽结合物的巯基尿酸的转化显着抑制后，在这两个物种逆行胆内输注的阿西维星，γ-谷氨酰转移酶活性的抑制剂。这些发现为巯基尿酸的肝内生物合成提供了直接证据。因此，肝细胞内合成的谷胱甘肽结合物分泌到胆汁中并分解为半胱氨酸结合物;后者随后可能被肝脏重吸收，N-乙酰化形成巯基尿酸并重新排泄到胆汁中。
Because of the low hepatic activity of gamma-glutamyl-transferase in the rat, the liver is generally considered to play only a minor role in the degradation of glutathione conjugates, a limiting step in mercapturic acid formation. Recent findings indicate, however, that the liver has a prominent role in glutathione catabolism, particularly in species other than rat. To examine the contributions of liver to mercapturic acid biosynthesis, mercapturate formation was compared in isolated perfused livers from rats and guinea pigs dosed with either 0.3 or 3.0 mumol of 1-chloro-2,4-dinitrobenzene (CDNB). Chemically synthesized glutathione conjugate, mercapturic acid, and intermediary metabolites of CDNB were used as standards in the high performance liquid chromatography analysis of bile and perfusate samples. Biliary excretion accounted for almost all of the recovered metabolites. A marked species difference was observed in the pattern of CDNB metabolism. Rat livers dosed with 0.3 mumol of CDNB excreted 55% of total biliary metabolites as the glutathione conjugate and 8.2% as the mercapturic acid, whereas guinea pig livers excreted only 4.8% as the glutathione conjugate and 47% as the mercapturate. Mercapturic formation was also dose-dependent, with a larger fraction formed at the 0.3- versus the 3.0-mumol dose (8.2 versus 3.7% in the rat; 47 versus 19% in the guinea pig). Hepatic conversion of the glutathione conjugate to the mercapturic acid was markedly inhibited in both species after retrograde intrabiliary infusion of acivicin, an inhibitor of gamma-glutamyltransferase activity. These findings provide direct evidence for intrahepatic biosynthesis of mercapturic acids. Thus, glutathione conjugates synthesized within hepatocytes are secreted into bile and broken down to cysteine conjugates; the latter are then presumably reabsorbed by the liver, N-acetylated to form the mercapturic acid and re-excreted into bile.