Determination of phase I metabolic enzyme activities in liver microsomes of Mrp2 deficient TR- and EHBR rats.
Determination of phase I metabolic enzyme activities in liver microsomes of Mrp2 deficient TR- and EHBR rats.
复制标题
测定 Mrp2 缺陷 TR- 和 EHBR 大鼠肝微粒体中 I 相代谢酶活性。
DOI：
10.1016/j.lfs.2005.01.020
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发表时间：
2005
期刊：
影响因子：
6.1
通讯作者：
D. C. Evans
中科院分区：
文献类型：
--
作者：
D. Newton;Regina W. Wang;D. C. Evans
小管多特异性有机阴离子转运蛋白/多药耐药蛋白2（cMOAT/Mrp 2）在阴离子外源性物质跨胆管膜转运中起主要作用。转运缺陷大鼠（TR-）和Mrp 2缺陷型高胆红素血症大鼠（EHBR）分别是Wistar和Sprague道利（SD）大鼠的突变体。在本研究中，将这些突变雄性和雌性大鼠制备的肝微粒体中的I相代谢酶活性与相应的非突变大鼠进行了比较。雄性和雌性TR大鼠的总细胞色素P450含量和NADPH-细胞色素P450还原酶活性均显著高于Wistar大鼠。在雄性TR−大鼠中，乙氧基试卤灵O-脱乙基化（EROD）、戊氧基试卤灵O-脱乙基化（PROD）、睾酮2α、7α和16 α-羟化酶活性较高，但睾酮6β-羟化酶活性和雄烯二酮形成率低于Wistar大鼠。雌性TR−大鼠的7α-羟化酶活性较高，但雌性Wistar大鼠的EROD活性较低。在EHBR与SD大鼠中进行的类似研究表明，雄性和雌性EHBR大鼠的总细胞色素P450含量增加; NADPH-细胞色素P450还原酶活性未受到显著影响。在雄性和雌性EHBR大鼠中观察到PROD活性和雄烯二酮形成率降低。雄性EHBR大鼠的睾酮6β-羟化酶活性低于雄性SD大鼠，而睾酮7α-羟化酶活性显著高于雄性和雌性EHBR大鼠。因此，除了Mrp 2缺陷，差异表达的α亚型及其对化合物的代谢和药代动力学的潜在影响时，应考虑解释这些大鼠品系的数据。
The canalicular multispecific organic anion transporter/multidrug resistance protein 2 (cMOAT/Mrp2) plays a major role in the transport of anionic xenobiotics across the bile canalicular membrane. Transport deficient rats (TR−) and Eisai-hyperbilirubinemic rats (EHBR), defective in Mrp2, are mutants of Wistar and Sprague Dawley (SD) rats, respectively. In this study, Phase I metabolic enzyme activities in liver microsomes prepared from these mutant male and female rats were compared to their corresponding non-mutant rats. The total cytochrome P450 contents and NADPH-cytochrome P450 reductase activity in male and female TR-rats were significantly higher than in Wistar rats. In male TR−rats, ethoxyresorufin O-deethylation (EROD), pentoxyresorufin O-deethylation (PROD), testosterone 2α, 7α and 16 α-hydroxylase activities were higher, but testosterone 6β-hydroxylase activity and the rate of androstenedione formation were lower than in Wistar rats. Female TR−rats had higher 7α-hydroxylase activity, but EROD activity was lower in female Wistar rats. Similar studies conducted in EHBR versus SD rats demonstrated increased total cytochrome P450 content in male and female EHBR rats; NADPH-cytochrome P450 reductase activity was not significantly affected. Decreased PROD activity and the rate of androstenedione formation were observed in male and female EHBR rats. Furthermore, testosterone 6β-hydroxylase activity was lower in male EHBR rats than in male SD rats while testosterone 7α-hydroxylase activity was significantly higher in male and female EHBR rats. Thus, in addition to Mrp2 deficiency, differential expression of CYP isoforms and their potential impact on the metabolism and pharmacokinetics of compounds should be considered when interpreting data from these rat strains.
影响因子：
2.9
作者：
WAXMAN, DJ;DANNAN, GA;GUENGERICH, FP
通讯作者：
GUENGERICH, FP