Zacharewski T, Harris M, Safe S
Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station 77843-4466.
Arch Biochem Biophys. 1989 Aug 1;272(2):344-55. doi: 10.1016/0003-9861(89)90228-2.
Treatment of rat hepatoma H-4-IIE cells in culture with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 2,3,7,8-tetrachlorodibenzofuran (TCDF), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 1,2,3,7,8-pentachlorodibenzofuran (PeCDF), 1,2,7,8-TCDF, and 2,3,7-trichlorodibenzo-p-dioxin (TrCDD) resulted in the structure-dependent induction of aryl hydrocarbon hydroxylase and ethoxyresorufin O-deethylase activities. The induction potencies followed the order 2,3,7,8-TCDD greater than 2,3,7,8-TCDF greater than 1,2,3,7,8-PeCDD approximately 1,2,3,7,8-PeCDF greater than 1,2,7,8-TCDF greater than 2,3,7-TrCDD and were comparable to structure-toxicity relationships which have previously been reported. In contrast, many of the properties of these compounds were structure-independent. For example, using tritiated congeners of high specific activity (greater than 30 Ci/mmol) the sedimentation coefficients (S) for the nuclear and cytosolic aryl hydrocarbon (Ah) receptor complexes were 5-6 and 9-10 S, respectively, for all the radioligands. Moreover, examination of the processing of nuclear Ah receptor complexes for the radiolabeled congeners showed that after 6 h, the rates of nuclear processing were very low and varied between 0.006 and 0.0385 fmol degraded/mg protein/mg total DNA. These results were consistent with the reported stability and persistence of the nuclear Ah receptor complexes and in addition, there were no apparent structure-dependent differences in the processing rates. Inspection of the nuclear receptor levels and the corresponding induced enzyme activities for the congeners showed that there was a linear correlation between average nuclear receptor complex levels (18-42 h) and induced enzyme activities (32-42 h) for all six radioligands; these data indicated that the rates of cytochrome P450-dependent gene expression correlated with the levels of nuclear Ah receptor complex. In contrast, the accumulation of occupied nuclear receptor complexes in rat hepatoma H-4-IIE cells was structure-dependent and appeared to be one of the factors which governed the observed structure-induction and the previously reported structure-toxicity relationships for 2,3,7,8-TCDD and related halogenated aryl hydrocarbons.
用2,3,7,8 - 四氯二苯并 - p - 二恶英（TCDD）、2,3,7,8 - 四氯二苯并呋喃（TCDF）、1,2,3,7,8 - 五氯二苯并 - p - 二恶英（PeCDD）、1,2,3,7,8 - 五氯二苯并呋喃（PeCDF）、1,2,7,8 - TCDF和2,3,7 - 三氯二苯并 - p - 二恶英（TrCDD）处理培养的大鼠肝癌H - 4 - IIE细胞，导致芳烃羟化酶和乙氧芴香豆素O - 脱乙基酶活性呈现结构依赖性诱导。诱导效力顺序为2,3,7,8 - TCDD＞2,3,7,8 - TCDF＞1,2,3,7,8 - PeCDD≈1,2,3,7,8 - PeCDF＞1,2,7,8 - TCDF＞2,3,7 - TrCDD，且与先前报道的结构 - 毒性关系相当。相比之下，这些化合物的许多性质与结构无关。例如，使用高比活（＞30 Ci/mmol）的氚化同系物，所有放射性配体的核和胞质芳烃（Ah）受体复合物的沉降系数（S）分别为5 - 6 S和9 - 10 S。此外，对放射性标记同系物的核Ah受体复合物加工过程的检查表明，6小时后，核加工速率非常低，在0.006至0.0385 fmol降解/毫克蛋白质/毫克总DNA之间变化。这些结果与报道的核Ah受体复合物的稳定性和持久性一致，此外，加工速率没有明显的结构依赖性差异。对同系物的核受体水平和相应诱导酶活性的检查表明，所有六种放射性配体的平均核受体复合物水平（18 - 42小时）与诱导酶活性（32 - 42小时）之间存在线性相关性；这些数据表明细胞色素P450依赖性基因表达速率与核Ah受体复合物水平相关。相比之下，大鼠肝癌H - 4 - IIE细胞中被占据的核受体复合物的积累是结构依赖性的，并且似乎是控制观察到的结构诱导以及先前报道的2,3,7,8 - TCDD和相关卤代芳烃的结构 - 毒性关系的因素之一。
