HEPATIC PROCESSING OF TRANSFORMING GROWTH-FACTOR-BETA IN THE RAT - UPTAKE, METABOLISM, AND BILIARY-EXCRETION
HEPATIC PROCESSING OF TRANSFORMING GROWTH-FACTOR-BETA IN THE RAT - UPTAKE, METABOLISM, AND BILIARY-EXCRETION
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DOI：
10.1172/jci113130
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发表时间：
1987-09-01
影响因子：
15.9
通讯作者：
LARUSSO, NF
中科院分区：
文献类型：
--
作者：
COFFEY, RJ;KOST, LJ;LARUSSO, NF
转化生长因子β（TGF β），最近发现的多肽调节正常和肿瘤细胞的生长。由于对TGF β的体内分布知之甚少，我们进行了研究以检查生物活性125 I-TGF β的肝加工。在老鼠。静脉注射后，125 I-TGF β.从血浆中消失，初始t1/2为2.2分钟;部分肝切除术延迟了125 I-TGF β的血浆消失。80%。股内注射后60分钟，63%的回收标记物存在于肝脏和/或胆汁中;到90分钟，大部分被肝脏去除的标记物（83%）已缓慢排泄到胆汁中。几乎所有的标记物（96%）可溶于三氯乙酸，而不是由特异性抗血清免疫沉淀。秋水仙碱和长春碱分别抑制了28%和37%的标记物的累积胆汁排泄;氯喹和亮抑酶肽各自增加了胆汁中标记物的量，所述标记物可被三氯乙酸沉淀并且与真实的125 I-TGF β共洗脱。分子筛色谱存在有效的125 I-TGF β的首过肝提取。(36%），其被未标记的TGF β抑制。(but而不是表皮生长因子，EGF）和凝集素以剂量依赖性方式;长期禁食也降低了清除率（26%）。通过差速或等密度离心分离肝脏后，放射性标记与溶酶体标记酶共分布。结果表明TGF β的快速、广泛、可重复和器官选择性提取。由肝。提取后，TGF β.经历有效的经鞘转运、广泛的细胞内代谢和其代谢物缓慢但完全的胆汁排泄。肝脏分馏研究和药理学操作表明，这些过程与细胞器，包括微囊和溶酶体。数据表明，肝脏是生物活性TGF β代谢的主要靶组织或部位。
Transforming growth factor beta (TGF.beta.), a recently discovered polypeptide, modulates growth of normal and neoplastic cells. Since little is known concerning in vivo disposition of TGF.beta., we performed studies to examine the hepatic processing of biologically active 125I-TGF.beta. in the rat. After intravenous injection, 125I-TGF.beta. disappeared from the plasma with an initial t1/2 of 2.2 min; partial hepatectomy delayed the plasma disappearance of 125I-TGF.beta. by 80%. 60 min after intrafemoral injection, 63% of the recovered label was present in liver and/or bile; by 90 min, most of the label removed by the liver (83%) had been slowly excreted into bile. Nearly all the label in the (96%) was soluble in trichloracetic acid and not immunoprecipitable by specific antiserum. Colchicine and vinblastine inhibited cumulative biliary excretion of label by 28 and 37%, respectively; chloroquine and leupeptin each increased the amount of label in bile that was precipitable by trichloracetic acid and that coeluted with authentic 125I-TGF.beta. on molecular sieve chromatography. There was efficient first-pass hepatic extraction of 125I-TGF.beta. (36%) in the isolated perfused rat liver, which was inhibited by unlabeled TGF.beta. (but not by epidermal growth factor, EGF) and by lectins in a dose-dependent manner; prolonged fasting also decreased clearance (26%). After fractionation of liver by differential or isopycnic centrifugation, radiolabel codistributed with marker enzymes for lysosomes. The results indicate rapid, extensive, inhibitable, and organselective extraction of TGF.beta. by the liver. After extraction, TGF.beta. undergoes efficient transhepatic transport, extensive intracellular metabolism, and slow but complete biliary excretion of its metabolites. Liver fractionation studies and pharmacologic manipulations suggest that these processes are associated with organelles that include microtobules and lysosomes. The data suggest that the liver is a major target tissue or site of metabolism for biologically active TGF.beta.