Pellizzer A M, Smid S A, Strasser S I, Lee C S, Mashford M L, Desmond P V
Department of Gastroenterology, St Vincent's Hospital, Fitzroy, Victoria, Australia.
J Gastroenterol Hepatol. 1996 Dec;11(12):1130-6. doi: 10.1111/j.1440-1746.1996.tb01841.x.
In both acute and chronic liver disease in man, elimination of drugs metabolized by the cytochrome P450 (CYP) enzymes is impaired. In contrast, those drugs metabolized by UDP-glucuronosyltransferase (UGT) have a relatively normal elimination. Studies in rats with experimentally induced liver injury also show this relative preservation of glucuronidation. In liver disease, a number of factors, including inflammation, fibrosis and regeneration, may be associated with this differential effect on drug metabolism. Partial hepatectomy provides a model in which to isolate the effects of liver regeneration on drug metabolism. Partial hepatectomy or sham operation was performed in 24 male Sprague-Dawley rats and three rats from each group were studied at days 1, 2, 4 and 6. Comparison between CYP and UGT was made at the protein level using immunohistochemistry and immunoblotting probed with a polyclonal antibody to UGT, identifying both family 1 and family 2 isoforms, and an antibody to the CYP isoform CYP2C11. Steady state messenger RNA levels of four isoforms of UGT were assessed by northern blot analysis. By both immunohistochemistry and immunoblotting, the level of CYP protein decreased from day 2 to 6 after hepatectomy. In contrast, the UGT protein level was not altered by partial hepatectomy. Northern blot analysis of UGT isoforms demonstrated differential regulation of isoforms from the two major families. The UGT family 1 isoforms were initially markedly depressed following partial hepatectomy and then steadily rose over 6 days to greater than the level in controls. In contrast, there was an apparent increase in UGT2B1 mRNA (not significant) on day 2, while UGT2B3 mRNA was maintained over the six days. These results demonstrate that during hepatic regeneration the protein content of total UGT is normal, while CYP2C11 protein is markedly reduced. Northern blot analysis suggests that individual isoforms of UGT are differentially regulated during the regeneration process.
在人类的急性和慢性肝病中，细胞色素P450（CYP）酶代谢的药物消除受损。相比之下，那些由尿苷二磷酸葡萄糖醛酸基转移酶（UGT）代谢的药物具有相对正常的消除。对实验性诱导肝损伤大鼠的研究也显示了葡萄糖醛酸化的这种相对保留。在肝病中，包括炎症、纤维化和再生在内的许多因素可能与对药物代谢的这种差异效应有关。部分肝切除术提供了一个分离肝再生对药物代谢影响的模型。对24只雄性Sprague-Dawley大鼠进行部分肝切除术或假手术，每组三只大鼠在第1、2、4和6天进行研究。使用免疫组织化学和用针对UGT的多克隆抗体进行免疫印迹在蛋白质水平上比较CYP和UGT，该抗体可识别1族和2族异构体，以及针对CYP异构体CYP2C11的抗体。通过Northern印迹分析评估UGT四种异构体的稳态信使RNA水平。通过免疫组织化学和免疫印迹，肝切除术后第2天至第6天CYP蛋白水平下降。相比之下，部分肝切除术未改变UGT蛋白水平。UGT异构体的Northern印迹分析表明两个主要家族的异构体受到不同调节。部分肝切除术后，UGT1族异构体最初明显降低，然后在6天内稳步上升至高于对照组水平。相比之下，UGT2B1 mRNA在第2天有明显增加（不显著），而UGT2B3 mRNA在6天内保持稳定。这些结果表明，在肝再生过程中，总UGT的蛋白质含量正常，而CYP2C11蛋白明显减少。Northern印迹分析表明，UGT的各个异构体在再生过程中受到不同调节。
