BINDING OF POLYCHLORINATED-BIPHENYLS CLASSIFIED AS EITHER PHENOBARBITONE-TYPE, 3-METHYLCHOLANTHRENE-TYPE OR MIXED-TYPE INDUCERS TO CYTOSOLIC AH RECEPTOR
BINDING OF POLYCHLORINATED-BIPHENYLS CLASSIFIED AS EITHER PHENOBARBITONE-TYPE, 3-METHYLCHOLANTHRENE-TYPE OR MIXED-TYPE INDUCERS TO CYTOSOLIC AH RECEPTOR
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DOI：
10.1016/0009-2797(82)90045-x
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发表时间：
1982-01-01
影响因子：
5.1
通讯作者：
OKEY, AB
中科院分区：
文献类型：
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作者：
BANDIERA, S;SAFE, S;OKEY, AB
据推测，可逆的，高亲和力的结合3-甲基胆蒽（MC）型诱导剂的受体蛋白（Ah受体）在大鼠肝细胞质中的芳烃羟化酶（AHH）的酶活性的诱导是必不可少的。研究了16种高纯度的合成氯代联苯（PCB）同系物的结合亲和力，这些同系物可分为苯巴比妥（PB）型、MC型或混合型（PB + MC）细胞色素P-450依赖性单加氧酶诱导剂。通过葡聚糖-活性炭处理后的蔗糖密度梯度分析，测定了联苯同系物与2，3，7，8-[3 H]四氯二苯并-对-二恶英（[3 H]TCDD）对特定胞质结合位点的竞争，从而确定了联苯同系物对受体的亲和力。该试验表明，受体与3，3“，4，4”，5-五氯联苯和3，3“，4，4”-四氯联苯（纯MC样诱导剂）的结合亲和力最高。混合型PCB诱导剂也与受体结合，但亲和力（平均EC 50值为8.6 μ M）低于3，3“，4，4”，5-五氯联苯;这与它们作为AHH诱导剂的相对较低的效力相对应。该受体在高浓度下结合2，2“，4，4”-四氯联苯、2，3，4，5-四氯联苯、2，2“，4，4”，5，5“-六氯联苯和2，3”，4，4“，5”，6-六氯联苯（0.1 mM）; PB未能结合，即使在10 mM。所有PCB竞争与[3 H]TCDD的Ah受体，但有一个很大的变化，其相对结合亲和力。事实上，2氯联苯类PB诱导剂和2氯联苯，而不是PB-或MC-型诱导剂竞争，再加上事实上，PB不结合受体表明，化学品以外的纯MC-型诱导剂绑定到胞质受体。结合的亲和力决定了给定PCB同系物作为细胞色素P-448诱导剂的相对效力。
It was postulated that reversible, high-affinity binding of 3-methylcholanthrene(MC)-type inducers to a receptor protein (the Ah receptor) in rat hepatic cytosol was essential for induction of aryl hydrocarbon hydroxylase (AHH) enzymic activity. The binding affinities of 16 highly-purified, synthetic chlorinated biphenyl (PCB) congeners, categorized as phenobarbitone(PB)-, MC- or mixed (PB + MC)-type inducers of cytochrome P-450-dependent monooxygenases were examined. The affinity of individual biphenyl congeners for the receptor was determined by their competition with 2,3,7,8-[3H]eterachlorodibenzo-p-dioxin ([3H]TCDD) for specific cytosolic binding sites as measured by sucrose density gradient analysis following dextran-charcoal treatment. This assay demonstrated that the receptor bound with highest affinity to 3,3'',4,4'',5-pentachlorobiphenyl and 3,3'',4,4''-tetrachlorobiphenyl (pure MC-like inducers). Mixed-type PCB inducers also bound to the receptor but with an affinity (average EC50 value of 8.6 .mu.M) lower than that for 3,3'',4,4'',5-pentachlorobiphenyl; this corresponded with their relatively lower potencies as AHH inducers. The receptor bounds 2,2'',4,4''-tetra-, 2,3,4,5-tetra-, 2,2'',4,4'',5,5''-hexa- and 2,3'',4,4'',5'',6-hexachlorobiphenyl at high concentrations (0.1 mM); PB failed to bind, even at 10 mM. All PCB competed with [3H]TCDD for Ah receptor but there was a great variation in their relative binding affinities. The fact that 2 chlorinated biphenyls classed as PB-like inducers and 2 chlorinated biphenyls which not PB- or MC-type inducers competed, coupled with the fact that PB did not bind to the receptor suggested that chemicals other than pure MC-type inducers bound to the cytosolic receptor. Affinity of the binding dictated the relative potency of given PCB congeners as inducers of cytochrome P-448.