Cytochrome P-450-dependent biotransformation of a series of phenoxazone ethers in the rat conceptus during early organogenesis: evidence for multiple P-450 isoenzymes.
Cytochrome P-450-dependent biotransformation of a series of phenoxazone ethers in the rat conceptus during early organogenesis: evidence for multiple P-450 isoenzymes.
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发表时间：
1988-07
影响因子：
3.6
通讯作者：
H. Yang;M. Namkung;M. Juchau
中科院分区：
文献类型：
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作者：
H. Yang;M. Namkung;M. Juchau
使用高度灵敏的探针-底物分析，对器官形成早期阶段大鼠孕体组织中药物生物转化的研究表明，三个独立的组织成分各自含有能够催化外源有机化学物质单氧合的 P-450 同工酶。胚胎本身的组织含有组成型P450，它们分别催化可测量的戊氧基苯恶宗和苄氧基苯恶宗的O-去戊基化和O-去苄基化，但没有可测量的甲氧基苯恶宗的O-去甲基化和几乎检测不到的乙氧基苯恶宗的O-去乙基化。在卵黄囊的制备物中测量了 O-脱戊基化和 O-脱苄基化反应的较高比活性，并且该器官似乎还含有组成型 P450(s)，用于容易检测乙氧基吩恶宗的 O-脱乙基化。在卵黄囊中无法检测到甲氧基苯恶宗的 O-去甲基化。在外胎盘锥组织中只能检测到O-脱苄基反应。用 3-甲基胆甾烯 (MC) 处理子宫内受孕，会导致卵黄囊和胚胎制剂中 O-脱乙基反应的发生率显着增加，但胎盘外胎盘却没有显着增加。在相同的制剂中未检测到去甲基化。用苯巴比妥、孕烯醇酮 16 α-甲腈或异黄樟素治疗对所研究的任何反应均未产生可观察到的影响。一氧化碳（CO:O2 = 80:20 对比 N2:O2 = 80:20）显着抑制所有反应速率，并且可以通过用 N2 替代 CO 来逆转抑制作用。 MC 诱导后，脱乙基化和脱苄基化受到抗 P450IA1 IgG 的抑制，但在未处理的受孕体内不受相同 IgG 部分的影响。在所用的任何条件下，去戊基化反应均不被抗P450IA1或抗P450IIB1/2抗体抑制。 1.0 µM 7,8-苯并黄酮强烈抑制 MC 处理的组织中的去乙基化，但未处理的胚胎组织则不然。美替酮 (0.1 mM) 未能显着抑制任何可测量的孕体催化的去戊基化反应。结果表明，在器官形成过程中，概念体组织中存在四种（或多种）功能性 P450 同工酶、卵黄囊和胚胎中存在组成型脱戊基酶、卵黄囊中存在组成型脱乙基酶、胚胎和卵黄囊中存在 MC 诱导型脱乙基酶以及所有三个中都存在组成型脱苄酶组织。即使在子宫内暴露于诱导剂后，在这三种组织中均未检测到 O-去甲基化。（摘要截断为 400 字）
Using highly sensitive probe-substrate analyses, investigations of drug biotransformation in tissues of the rat conceptus during an early stage of organogenesis revealed that three separate tissue components each contained P-450 isozymes capable of catalyzing the monooxygenation of foreign organic chemicals. Tissues of the embryo proper contained constitutive P450(s) that catalyzed readily measurable O-depentylation and O-debenzylation of pentoxyphenoxazone and benzyloxyphenoxazone, respectively, but no measurable O-demethylation of methoxyphenoxazone and barely detectable O-deethylation of ethoxyphenoxazone. Higher specific activities for the O-depentylation and O-debenzylation reactions were measured in preparations of the yolk sac and this organ also appeared to contain constitutive P450(s) for the readily detectable O-deethylation of ethoxyphenoxazone. The O-demethylation of methoxyphenoxazone could not be detected in the yolk sac. Only the O-debenzylation reaction could be detected in tissues of the ectoplacental cone. Treatment of conceptuses in utero with 3-methycholantherene (MC) resulted in significantly increased rates of O-deethylation reactions in preparations of yolk sac and embryo but not ectoplacental cone. Demethylation was not detectable in the same preparations. Treatment with phenobarbital, pregnenolone-16 alpha-carbonitrile, or isosafrole produced no observable effect on any of the reactions studied. Carbon monoxide (CO:O2 = 80:20 versus N2:O2 = 80:20) markedly inhibited all reaction rates and inhibition could be reversed by replacement of CO with N2. Deethylation and debenzylation were inhibited by anti-P450IA1 IgG after MC induction but were not affected by the same IgG fraction in untreated conceptuses. Depentylation reactions were not inhibited by anti-P450IA1 or anti-P450IIB1/2 antibodies under any of the conditions used. Deethylation was strongly inhibited by 1.0 microM 7,8-benzoflavone in tissues from MC-treated but not untreated conceptus. Metyrapone (0.1 mM) failed to significantly inhibit any of the measurable conceptus-catalyzed depentylation reaction. The results indicated the presence of four (or more) functional P450 isozymes in tissues of the conceptus during organogenesis, a constitutive depentylase(s) in the yolk sac and embryo, a constitutive deethylase(s) present in the yolk sac, an MC-inducible deethylase(s) in the embryo and yolk sac, and constitutive debenzylase(s) present in all three tissues. No O-demethylation was detectable in any of the three tissues, even after in utero exposure to inducers.(ABSTRACT TRUNCATED AT 400 WORDS)