EFFECTS OF HYPERBILIRUBINEMIA ON GLUTATHIONE-S-TRANSFERASE ISOENZYMES IN CEREBELLAR CORTEX OF THE GUNN RAT
EFFECTS OF HYPERBILIRUBINEMIA ON GLUTATHIONE-S-TRANSFERASE ISOENZYMES IN CEREBELLAR CORTEX OF THE GUNN RAT
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DOI：
10.1042/bj2910453
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发表时间：
1993-04-15
影响因子：
4.1
通讯作者：
SIEGEL, FL
中科院分区：
文献类型：
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作者：
JOHNSON, JA;HAYWARD, JJ;SIEGEL, FL
谷胱甘肽S转移酶(GSTs)是一个同工酶家族，参与了多种亲电性外源物质的解毒过程。结果表明，高胆红素血症组大鼠小脑皮质GST活性和胞浆GSTs浓度均高于非黄褐证对照组。Gunn大鼠小脑皮质的GST同工酶存在年龄依赖性和区域特异性升高，而脑干、丘脑/下丘脑、皮质和肝脏的GST浓度无明显变化。Gunn大鼠20日龄时，胞浆GST活性在小叶和外侧半球是正常大鼠的1.3倍，60d龄Gunn大鼠的小叶、侧半球和蠕虫GST活性是非黄疸大鼠的1.7倍。H.P.L.C.用来测定从有黄褐斑和非黄褐斑动物的肝脏和脑区域分离的胞浆部分中GST亚单位蛋白的浓度。20日龄小脑各区α类GST亚基2(Y(C1)；3.0倍)和8(Y(K)；2.0倍)的水平在黄褐斑大鼠均升高。60日龄黄褐斑动物小脑皮质内α类GST亚基2(Y(C1)；5.0倍)和8(Y(K)；3.0倍)、Mu类亚基11(Y(O)；2.5倍)和Pi类亚基7(Y(P)；2.0倍)的浓度均升高。在10日龄、20日龄和60日龄无黄斑和有黄斑Gunn大鼠的小脑中，Mu类GST亚单位4(Y(B2))的浓度最高，蠕虫最低；高胆红素血症使20日龄和60日龄大鼠小脑叶和侧半球的Mu类GST亚单位4(Y(B2)；3~5倍)的浓度增加，但不能使蚯蚓的浓度增加。腹腔注射磺胺二甲氧嘧啶，一种长效的磺胺类药物，可取代白蛋白结合部位的胆红素，并增加组织中的胆红素水平，进一步增加高胆红素血症大鼠小脑皮质外侧区域本已升高的GST亚单位的浓度。例如，注射生理盐水的Gunn大鼠的4亚单位(Y(B2))浓度(Y(B2))是无黄斑对照组的2.2倍，注射100毫克/公斤体重的磺胺二甲氧嘧啶的大鼠是对照组的7.4倍。相比之下，磺胺二甲氧嘧啶注射剂对黄褐斑动物蠕虫中的GST无影响。磺胺二甲氧嘧啶对杂合子(JJ)Gunn大鼠外侧区和蠕虫的GST浓度无影响。在Gunn大鼠中，这些区域特异性GST蛋白浓度的改变与先前报道的区域特异性小脑发育不良呈负相关。其他研究表明，浦肯野细胞在小脑蚯蚓中受到严重影响，而存在于外侧半球和小叶的神经元受到的影响较小；这些对小脑皮层的影响因注射磺胺二甲氧嘧啶而加剧。因此，我们的数据表明，区域特异性GST的表达可能对内源性和/或外源性神经毒剂具有保护作用。
The glutathione S-transferases (GSTs) are a family of isoenzymes involved in the detoxication of a variety of electrophilic xenobiotics. The present investigation demonstrates that GST activity and the concentration of cytosolic GSTs in cerebellar cortex of Gunn rats were increased in hyperbilirubinaemic animals compared with non-jaundiced controls. Age-dependent and region-specific increases in GST isoenzymes were seen in three regions of the cerebellar cortex of jaundiced Gunn rats, whereas GST concentrations were not altered in the brainstem, thalamus/hypothalamus, cortex or liver. Cytosolic GST activity was increased 1.3-fold in the flocculus and lateral hemispheres of 20-day-old and 1.7-fold in the flocculus, lateral hemispheres and vermis of 60-day-old jaundiced (jj; homozygous) Gunn rats compared with non-jaundiced (Jj; heterozygous) Gunn rats. H.p.l.c. was used to determine the GST subunit protein concentrations in cytosolic fractions isolated from liver and brain regions of jaundiced and non-jaundiced animals. In all regions of the cerebellum from 20-day-old animals, the levels of Alpha-class GST subunits 2 (Y(c1); 3.0-fold) and 8 (Y(k); 2.0-fold) were increased in jaundiced rats. In 60-day-old animals, the concentrations of Alpha-class GST subunits 2 (Y(c1); 5.0-fold) and 8 (Y(k); 3.0-fold), Mu-class subunit 11 (Y(o); 2.5-fold) and Pi-class subunit 7 (Y(p); 2.0-fold) were increased in all regions of cerebellar cortex of jaundiced animals. In cerebellum of 10-, 20- and 60-day-old non-jaundiced and jaundiced Gunn rats, the flocculus had the highest concentration of Mu-class GST subunit 4 (Y(b2)) and vermis the lowest; hyperbilirubinaemia increased the concentration of subunit 4 (Y(b2); 3- to 5-fold) in the flocculus and lateral hemispheres, but not the vermis, of 20- and 60-day-old rats. Intraperitoneal injection of sulphadimethoxine, a long-acting sulphonamide which displaces bilirubin from its albumin-binding sites and increases the bilirubin levels in tissues, further increased the already elevated concentrations of GST subunits in the lateral regions of cerebellar cortex of hyperbilirubinaemic rats. For example, the concentration of subunit 4 (Y(b2)) was increased 2.2-fold (compared with non-jaundiced controls) in Gunn rats injected with saline and 7.4-fold in rats injected with 100 mg of sulphadimethoxine/kg body weight. In contrast, GSTs in the vermis of jaundiced animals were not affected by sulphadimethoxine injection. Sulphadimethoxine had no effect on GST concentrations in lateral regions and vermis of heterozygous (Jj) Gunn rats. These region-specific alterations in GST protein concentrations are inversely related to previously documented region-specific cerebellar hypoplasia in Gunn rats. Others have shown that Purkinje cells are severely affected in the cerebellar vermis, whereas neurons present in the lateral hemispheres and flocculi were less affected; these effects on the cerebellar cortex were exacerbated by sulphadimethoxine injection. Our data thus suggest that region-specific GST expression may confer protection against endogenous and/or exogenous neurotoxic agents.