Carpenter H M, Curtis L R
Oak Creek Laboratory of Biology, Department of Fisheries and Wildlife. Oregon State University, Corvallis 97331.
Drug Metab Dispos. 1991 May-Jun;19(3):673-8.
Pretreatment of mice with low doses of chlordecone (CD) alters the pattern of distribution of a subsequent tracer dose of [14C]CD. We call this preexposure effect a pretreatment disposition response (PDR) and suggest that it reflects important cellular responses to lipophilic compounds. The present study examined three possible mechanisms for CD-induced PDR (CD-PDR). The first was that CD-PDR occurred with induction of the cytochrome P-450 system. A cumulative dose of 45 mg/kg CD caused a PDR, increased the content of cytochrome P-450, and elevated the activities of ethoxyresorufin- and ethoxycoumarin-O-deethylases (EROD and ECOD). A cumulative dose of 10 mg/kg caused a PDR, but did not affect cytochrome P-450, EROD, or ECOD, indicating that an induction of the cytochrome P-450 system in not necessary for PDR. A second possibility examined was that CD-PDR resulted because of an altered affinity of a subcellular fraction. Following a pretreatment regimen designed to produce PDR, amounts of [14C]CD in each fraction paralleled homogenate values in the liver and the kidney. However, when values were calculated as percentages of total label recovered, it was apparent that [14C]CD levels were higher in the microsomal fraction of the liver. Finally, the possibility that CD-PDR occurred because of an interaction of CD with proteins involved in cholesterol synthesis and transport was addressed. CD pretreatment increased disposition of a dose of [14C]cholesterol to the fat at the expense of [14C]cholesterol in the liver and kidney.
用低剂量开蓬（CD）对小鼠进行预处理会改变随后给予的示踪剂量[14C]CD的分布模式。我们将这种预暴露效应称为预处理处置反应（PDR），并认为它反映了细胞对亲脂性化合物的重要反应。本研究探讨了CD诱导的PDR（CD-PDR）的三种可能机制。第一种是CD-PDR是由细胞色素P-450系统的诱导引起的。累积剂量为45mg/kg的CD引起了PDR，增加了细胞色素P-450的含量，并提高了乙氧芴香豆素-O-脱乙基酶和乙氧香豆素-O-脱乙基酶（EROD和ECOD）的活性。累积剂量为10mg/kg引起了PDR，但不影响细胞色素P-450、EROD或ECOD，这表明细胞色素P-450系统的诱导对于PDR不是必需的。研究的第二种可能性是，CD-PDR是由于亚细胞组分的亲和力改变所致。在采用旨在产生PDR的预处理方案后，肝脏和肾脏中各组分的[14C]CD含量与匀浆值平行。然而，当将数值计算为回收的总标记物的百分比时，很明显肝脏微粒体组分中的[14C]CD水平较高。最后，探讨了CD-PDR是由于CD与参与胆固醇合成和转运的蛋白质相互作用而发生的可能性。CD预处理增加了剂量的[14C]胆固醇向脂肪的处置，同时减少了肝脏和肾脏中[14C]胆固醇的含量。
