Comparative pharmacodynamics of CYP2B induction by DDT, DDE, and DDD in male rat liver and cultured rat hepatocytes.
Comparative pharmacodynamics of CYP2B induction by DDT, DDE, and DDD in male rat liver and cultured rat hepatocytes.
复制标题
DDT、DDE 和 DDD 在雄性大鼠肝脏和培养大鼠肝细胞中诱导 CYP2B 的药效学比较。
DOI：
10.1080/009841098159187
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Kocarek,TA
中科院分区：
文献类型：
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作者：
Nims,RW;Lubet,RA;Fox,SD;Jones,CR;Thomas,PE;Reddy,AB;Kocarek,TA
本文研究了农药DDT [1，1，1-三氯-2，2-二]对大鼠肝细胞色素P450 2B（CYP 2B）的诱导作用对氯苯基乙烷]及其代谢产物DDE \[1，1-二氯-2，2-二（对氯苯基）乙烯]，其是生物保留的，和DDD \[1，1-二氯-2，2-双（对氯苯基）乙烷]，其被进一步代谢，因此不易于生物累积。在雄性F344/NCr大鼠中，发现DDT、DDE和DDD均为纯苯巴比妥型细胞色素P-450诱导剂，可诱导肝脏CYP 2B和CYP 3A，但不诱导CYP 1A。DDT、DDE和DDD诱导CYP 2B（苄氧基试卤灵O -脱烷基化）的ED 50值在饮食中分别为103、88和620 ppm（暴露14天）。与对照值相比，DDT、最大DDE和DDD诱导苄氧基试卤灵O -脱烷基化的效力（E值）分别为24、22和21倍。三种同系物对CYP 2B诱导的效力似乎也相似，EC 50值（基于血清DDT总当量）分别为1.5、1.8和0.51 μ M。基于肝组织中DDT当量的EC 50值分别为15、16和5.9 mumol/kg肝组织。在成年大鼠肝细胞的原代培养物中，DDT、DDE和DDD均显示出诱导编码CYP 2B的总细胞RNA的能力（ED 50值分别为0.98、0.83和2.7 μ M）。这些结果表明，DDT，DDE，DDD都具有高度的内在CYP 2B诱导大鼠肝脏的能力，尽管显着差异，在生物滞留之间的同源物。
In this study the pharmacodynamics were characterized of rat hepatic cytochrome P450 2B (CYP2B) induction by the pesticide DDT \[1,1,1-trichloro-2,2-bis(p -chlorophenyl) ethane] and its metabolites DDE \[1,1-dichloro-2,2-bis(p -chlorophenyl)ethylene], which is bioretained, and DDD \[1,1-dichloro-2,2-bis(p -chlorophenyl)ethane], which is metabolized further and therefore less prone to bioaccumulate. DDT, DDE, and DDD were each found to be pure phenobarbital-type cytochrome P-450 inducers in the male F344/NCr rat, causing induction of hepatic CYP2B and CYP3A, but not CYP1A. The ED50 values for CYP2B induction ( benzyloxyresorufin O -dealkylation) by DDT, DDE, and DDD were, respectively, 103, 88, and 620 ppm in diet (14 d of exposure). The efficacies ( E values) for induction of benzyloxyresorufin O -dealkylation by DDT, max DDE, and DDD were 24-, 22-, and 21-fold, respectively, compared to control values. The potencies of the three congeners for CYP2B induction appeared also to be similar, with EC50 values (based on total serum DDT equivalents) of 1.5, 1.8, and 0.51 mu M, respectively. The EC50 values based on DDT equivalents in hepatic tissue were 15, 16, and 5.9 mumol/kg liver tissue, respectively. In primary cultures of adult rat hepatocytes, DDT, DDE, and DDD each displayed ability to induce total cellular RNA coding for CYP2B (ED50 values of 0.98, 0.83, and 2.7 mu M , respectively). These results suggest that DDT, DDE, and DDD each possess a high degree of intrinsic CYP2B-inducing ability for rat liver, despite marked differences in bioretention among the congeners.