Genetic Expression of Aryl Hydrocarbon Hydroxylase by 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Evidence for a Receptor Mutation in Genetically Non-responsive Mice
Genetic Expression of Aryl Hydrocarbon Hydroxylase by 2,3,7,8-Tetrachlorodibenzo-p-dioxin: Evidence for a Receptor Mutation in Genetically Non-responsive Mice
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2,3,7,8-四氯二苯并-对二恶英对芳基烃羟化酶的遗传表达：遗传无反应小鼠中受体突变的证据
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发表时间：
1975
期刊：
影响因子：
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通讯作者：
E. Glover
中科院分区：
文献类型：
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作者：
A. Poland;E. Glover
2,3,7,8-四氯二苯并-对二恶英（TCDD）可诱导小鼠肝脏芳烃羟化酶活性。基因上“无反应”的小鼠对常见的芳香烃（如3-甲基胆蒽）没有反应，是由TCDD诱导的；然而，所需的剂量比基因上“有反应”的菌株要大。对C57BL/6J、BALB/cJ和A/J有反应的菌株，TCDD能激发一半最大酶活性（ED50）的剂量约为1 nmol /kg，对DBA/2J、AKR/J和SJL/J无反应的菌株，TCDD的ED50至少为10 nmol /kg。在上述菌株中，3 nmol /kg的TCDD不能诱导无应答小鼠的肝芳烃羟化酶活性，但能诱导应答小鼠的最大酶活性的70%或更多。在14个自交系小鼠中，3-甲基胆蒽（0.3 mmol /kg）和TCDD （3 mmol /kg）均能很好地检测到芳烃响应性和不响应性的表型特征。在所有无反应菌株中，高10倍剂量的TCDD诱导肝酶活性。C57BL/6J和DBA/2J亲本杂合后代对TCDD具有中等敏感性。我们从这些数据中得出结论，基因无反应的小鼠具有表达芳烃羟化酶所需的结构和调控基因。无反应小鼠的缺陷最可能的解释似乎是一种突变，导致诱导受体位点对诱导药物的亲和力降低，导致对3-甲基蒽几乎完全无反应，对更有效的诱导剂TCDD的敏感性降低。
Hepatic aryl hydrocarbon hydroxylase activity is induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in all inbred strains of mice tested. The genetically "nonresponsive" strains of mice which fail to respond to the usual aromatic hydrocarbons (e.g., 3-methylcholanthrene) are induced by TCDD; however, the dose required is greater than for the genetically "responsive" strains. The dose of TCDD that elicits half the maximal enzyme activity (ED50) in responsive strains, C57BL/6J, BALB/cJ, and A/J, is approximately 1 nmole/kg, and in the nonresponsive strains, DBA/2J, AKR/J, and SJL/J, the ED50 is at least 10 nmoles/kg. In the above strains, TCDD at 3 nmoles/kg fails to induce hepatic aryl hydrocarbon hydroxylase activity in nonresponsive mice, but elicits 70% or more of the observed maximal enzyme activity in responsive strains. In 14 inbred strains of mice, the phenotypic characteristic of aromatic hydrocarbon responsiveness or nonresponsiveness can be detected equally well by a challenge with 3-methylcholanthrene (0.3 mmole/kg) or TCDD at 3 nmoles/kg. In all nonresponsive strains, a 10-fold higher dose of TCDD induces hepatic enzyme activity. The heterozygous offspring of C57BL/6J and DBA/2J parents are distinguishable from both parental strains by an intermediate sensitivity to TCDD. We conclude from these data that the genetically nonresponsive mice have the structural and regulatory genes necessary for the expression of aryl hydrocarbon hydroxylase. The most likely explanation of the defect in nonresponsive mice appears to be a mutation which results in an induction receptor site with a diminished affinity for inducing drugs, leading to an almost absolute unresponsiveness to 3-methyicholanthrene and a diminished sensitivity to the more potent inducer, TCDD.