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首页> 外文期刊>Drug Metabolism and Disposition: The Biological Fate of Chemicals >Mechanism of induction of cytochrome p450 enzymes by the proestrogenic endocrine disruptor pesticide-methoxychlor: interactions of methoxychlor metabolites with the constitutive androstane receptor system.
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Mechanism of induction of cytochrome p450 enzymes by the proestrogenic endocrine disruptor pesticide-methoxychlor: interactions of methoxychlor metabolites with the constitutive androstane receptor system.

机译：促雌激素性内分泌干扰物农药-甲氧基氯诱导细胞色素p450酶的机制：甲氧基氯代谢物与组成型雄烷受体系统的相互作用。

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Methoxychlor, a structural analog of the DDT pesticide, was previously shown to induce rat hepatic CYP2B and -3A mRNAs and the corresponding proteins [J Biochem Mol Toxicol 1998;12:315-323], Additionally, methoxychlor was found to activate the constitutive androstane receptor (CAR) system and induce CYP2B6 (J Biol Chem 1999;274:6043-6046), suggesting a mechanism for methoxychlor-mediated cytochrome P450 (P450) 2B induction. However, it has not been established whether CAR activation and P450 induction was due to methoxychlor per se and/or due to its metabolites. Also, a possible link between the estrogenic potency of methoxychlor metabolites and CAR activation or P450 induction was not investigated. The current study explores the ability of methoxychlor and its metabolites to activate CAR and whether their potency of CAR activation correlates with their respective estrogenicity. Methoxychlor and its metabolites [mono-OH-M [1,1,1-trichloro-2 (4-hydroxyphenyl)-2'-(4-methoxyphenyl)ethane]; bis-OH-M [1,1,1-trichloro-2,2'-bis(4-hydroxyphenyl)ethane]; ring-OH-M [1,1,1-trichloro-2(4-methoxyphenyl)-2'-(3-hydroxy-4-methoxyphenyl)ethane]; and tris-OH-M [1,1,1-trichloro-2(4-hydroxyphenyl)-2'-(3,4-dihydroxyphenyl)ethane]] were found to be potent activators of CAR. Dose response curves indicated that tris-OH-M is a more potent CAR activator than methoxychlor, mono-OH-M, and bis-OH-M. Since tris-OH-M is a much weaker estrogen receptor-alpha agonist than mono-OH-M and bis-OH-M, it seems that estrogenicity is not a significant factor in CAR activation. These findings indicate that alteration of methoxychlor-benzene rings, i.e., generation of phenolic constituents, does not appreciably alter CAR activation and suggest that a common structural motif in the methoxychlor class of compounds controls CAR activation. Studies are needed to identify the structural motif necessary for CAR activation and CYP2B induction.
机译：以前显示滴滴涕农药的结构类似物甲氧基氯可诱导大鼠肝脏CYP2B和-3A mRNA和相应的蛋白质[J Biochem Mol Toxicol 1998; 12：315-323]，此外，还发现甲氧基氯可激活组成型雄烷烃受体（CAR）系统并诱导CYP2B6（J Biol Chem 1999; 274：6043-6046），提示甲氧基氯介导的细胞色素P450（P450）2B诱导机制。然而，尚未确定CAR活化和P450诱导是由于甲氧基氯本身和/或由于其代谢产物。同样，未研究甲氧基氯代谢产物的雌激素效价与CAR活化或P450诱导之间的可能联系。当前的研究探讨了甲氧基氯及其代谢物激活CAR的能力，以及它们的CAR激活能力是否与其各自的雌激素性相关。甲氧氯及其代谢物[单-OH-M [1,1,1-三氯-2（4-羟基苯基）-2'-（4-甲氧基苯基）乙烷];双-OH-M [1,1,1-三氯-2,2'-双（4-羟苯基）乙烷];环-OH-M [1,1,1-三氯-2（4-甲氧基苯基）-2'-（3-羟基-4-甲氧基苯基）乙烷];发现tris-OH-M [1,1,1-三氯-2（4-羟基苯基）-2'-（3,4-二羟基苯基）乙烷]是CAR的有效活化剂。剂量响应曲线表明，tris-OH-M是一种比甲氧基氯，mono-OH-M和bis-OH-M更有效的CAR活化剂。由于tris-OH-M是比mono-OH-M和bis-OH-M弱得多的雌激素受体-α激动剂，因此雌激素作用似乎不是CAR活化的重要因素。这些发现表明甲氧基氯-苯环的改变，即酚类成分的产生，不会明显改变CAR的活化作用，并表明甲氧基氯类化合物中的常见结构基序控制了CAR的活化。需要进行研究以鉴定CAR激活和CYP2B诱导所必需的结构基序。

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