Methoxyresondin: An inappropriate substrate for CYP1A2 in the mouse
Methoxyresondin: An inappropriate substrate for CYP1A2 in the mouse
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DOI：
10.1016/s0006-2952(98)00241-x
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发表时间：
1998-12-15
影响因子：
5.8
通讯作者：
Birnbaum, LS
中科院分区：
文献类型：
--
作者：
Hamm, JT;Ross, DG;Birnbaum, LS
肝微粒体来自Cyp 1a 2（-/-）敲除（KO）和亲代小鼠品系，C57 BL/6 N和129 Sv，用于检查甲氧试卤灵和乙酰苯胺作为CYP 1A 2活性底物的特异性。此外，将每组动物暴露于CYP 1诱导化合物。与预期一致，未处理1a 2 KO小鼠的微粒体不具有免疫可检测的CYP 1A 2蛋白;然而，甲氧基试卤灵-O-脱甲基酶（MROD，25.5 +/- 6.1 pmol/min/mg蛋白）和乙酰苯胺-4-羟基化（ACOH，0.64 +/- 0.04 nmol/min/mg蛋白）活性仍然存在。此外，2，3，7，8-四氯二苯并-p-二恶英（TCDD）诱导1a 2 KO小鼠中的乙氧基试卤灵-O-脱乙基酶（EROD），伴随着MROD活性增加70倍以上。相反，ACOH仅被TCDD诱导2倍。与1a 2基因敲除小鼠一样，暴露于TCDD或2，3，4，7，8-五氯二苯并呋喃（4-PeCDF）的亲本品系显示出大量EROD和MROD诱导，而ACOH活性诱导程度较低。PCB 153（2，2 '，4，4'，5，5 '-六氯联苯）导致低水平的EROD和MROD诱导。结果表明，这两种底物都受到非CYP 1A 2来源的代谢，CYP 1A 1活性对甲氧基试卤灵代谢的明显贡献使得MROD不适合区分小鼠中的CYP 1A 1和CYP 1A 2活性。生物化学制药56;12：1657-1660，1998年。(C)1998年爱思唯尔科学公司
Hepatic microsomes derived from Cyp1a2(-/-) knockout (KO) and parental strains of mice, C57BL/6N and 129Sv, were used to examine the specificity of methoxyresorufin and acetanilide as substrates for CYP1A2 activity. In addition, animals from each group were exposed to CYP1-inducing compounds. As expected, microsomes from untreated 1a2 KO mice did not have immunodetectable CYP1A2 protein; however, methoxyresorufin-O-demethylase (MROD, 25.5 +/- 6.1 pmol/min/mg protein) and acetanilide-4-hydroxylation (ACOH, 0.64 +/- 0.04 nmol/min/mg protein) activities were still present. Furthermore, induction of ethoxyresorufin-O-deethylase (EROD) by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 1a2 KO mice was accompanied by a greater than 70-fold increase in MROD activity. In contrast, ACOH was only induced 2-fold by TCDD. As with 1a2 KO mice, the parental strains exposed to TCDD or 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF) showed substantial EROD and MROD induction, whereas ACOH activity was induced to a lesser degree. PCB153 (2,2',4,4',5,5'-hexachlorobiphenyl) resulted in low levels of both EROD and MROD induction. Results indicate that both substrates are subject to metabolism by non-CYP1A2 sources, and the apparent contribution of CYP1A1 activity to methoxyresorufin metabolism makes MROD unsuitable for differentiating CYP1A1 and CYP1A2 activities in the mouse. BIOCHEM PHARMACOL 56;12:1657-1660, 1998. (C) 1998 Elsevier Science Inc.