Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals,Environmental Science & Technology

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Molecular Mechanism of Alternative P450-Catalyzed Metabolism of Environmental Phenolic Endocrine-Disrupting Chemicals
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2018-03-12 00:00:00 , DOI: 10.1021/acs.est.8b00601
Li Ji _{1,

2} , Shujing Ji ₁ , Chenchen Wang ₁ , Kasper P. Kepp ₃

Affiliation

Understanding the bioactivation mechanisms to predict toxic metabolites is critical for risk assessment of phenolic endocrine-disrupting chemicals (EDCs). One mechanism involves ipso-substitution, which may contribute to the total turnover of phenolic EDCs, yet the detailed mechanism and its relationship with other mechanisms are unknown. We used density functional theory to investigate the P450-catalyzed ipso-substitution mechanism of the prominent xenoestrogen bisphenol A. The ipso-substitution proceeds via H-abstraction from bisphenol A by Compound I, followed by essentially barrierless OH-rebound onto the ipso-position forming a quinol, which can spontaneously decompose into the carbocation and hydroquinone. This carbocation can further evolve into the highly estrogenic hydroxylated and dimer-type metabolites. The H-abstraction/OH-rebound reaction mechanism has been verified as a general reaction mode for many other phenolic EDCs, such as bisphenol analogues, alkylphenols and chlorophenols. The identified mechanism enables us to effectively distinguish between type I (eliminating-substituent as anion) and type II (eliminating-substituent as cation) ipso-substitution in various phenolic EDCs. We envision that the identified pathways will be applicable for prediction of metabolites from phenolic EDCs whose fate are affected by this alternative type of P450 reactivity, and accordingly enable the screening of these metabolites for endocrine-disrupting activity.

中文翻译：

替代P450催化破坏环境的酚类内分泌化学物质的代谢的分子机理

了解生物激活机制以预测有毒代谢物对于酚类内分泌干扰化学物质（EDC）的风险评估至关重要。一种机制涉及ipso取代，它可能有助于酚类EDC的总营业额，但其详细机制及其与其他机制的关系尚不清楚。我们使用密度泛函理论研究了主要异种雌激素双酚A的P450催化的ipso取代机理。ipso取代是通过化合物I通过双酚A的H吸收进行的，然后通过基本上无障碍的OH反弹到ipso位置形成可以自发分解为碳正离子和对苯二酚的喹诺醇。这种碳正离子可进一步演变成高度雌激素的羟基化和二聚体型代谢产物。氢吸收/ OH反弹反应机理已被证实是许多其他酚类EDC的通用反应模式，例如双酚类似物，烷基酚和氯酚。所确定的机制使我们能够有效地区分各种酚类EDC中的I型（消除取代基为阴离子）和II型（消除取代基为阳离子）ipso取代。我们设想，已确定的途径将可用于预测其命运受另一种P450反应性影响的酚类EDC的代谢产物，并因此能够筛选这些代谢产物的内分泌干扰活性。所确定的机制使我们能够有效地区分各种酚类EDC中的I型（消除取代基为阴离子）和II型（消除取代基为阳离子）ipso取代。我们设想，已确定的途径将可用于预测其命运受另一种P450反应性影响的酚类EDC的代谢产物，并因此能够筛选这些代谢产物的内分泌干扰活性。所确定的机制使我们能够有效地区分各种酚类EDC中的I型（消除取代基为阴离子）和II型（消除取代基为阳离子）ipso取代。我们设想，已确定的途径将可用于预测其命运受另一种P450反应性影响的酚类EDC的代谢产物，并因此能够筛选这些代谢产物的内分泌干扰活性。

更新日期：2018-03-13

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