Enantioselective Distribution, Degradation, and Metabolite Formation of Myclobutanil and Transcriptional Responses of Metabolic-Related Genes in Rats,Environmental Science & Technology

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Enantioselective Distribution, Degradation, and Metabolite Formation of Myclobutanil and Transcriptional Responses of Metabolic-Related Genes in Rats
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2018-07-16 , DOI: 10.1021/acs.est.8b01721
Weiyu Hao _{1,

2} , Xiao Hu _{1,

2} , Feilong Zhu _{1,

2} , Jing Chang _{1,

2} , Jitong Li ₁ , Wei Li ₁ , Huili Wang ₁ , Baoyuan Guo ₁ , Jianzhong Li ₁ , Peng Xu ₁ , Yanfeng Zhang ₁

Affiliation

Myclobutanil (MT), a chiral fungicide, can be metabolized enantioselectively in organisms. In this work, the associated absorption, distribution, metabolism and transcriptional responses of MT in rats were determined following a single-dose (10 mg·kg^–1 body weight) exposure to rac-, (+)- or (−)-MT. The enantiomer fractions (EFs) were less than 0.5 with time in the liver, kidney, heart, lung, and testis, suggesting preferential enrichment of (−)-MT in these tissues. Furthermore, there was conversion of (+)-form to (−)-form in the liver and kidney after 6 h exposure to enantiopure (+)-MT. Enrichment and degradation of the two enantiomers differed between rac-MT and MT-enantiomers groups, suggesting that MT bioaccumulation is enantiomer-specific. Interestingly, the degradation half-life of MT in the liver with rac-MT treatment was shorter than that with both MT-enantiomer treatments. One reason may be that the gene expression levels of cytochrome P450 1a2 (cyp1a2) and cyp3a2 genes in livers treated with rac-MT were the highest among the three exposure groups. In addition, a positive correlation between the expression of cyp2e1 and cyp3a2 genes and rac-MT concentration was found in livers exposed to rac-MT. Simultaneously, five chiral metabolites were detected, and the enantiomers of three metabolites, RH-9090, RH-9089, and M2, were separated. The detected enantiomers of (+)-MT metabolites were in complete contrast with those of (−)-MT metabolites. According to the results, a metabolic pathway of MT in male rats was proposed, which included the following five metabolites: RH-9089, RH-9090, RH-9090 Sulfate, M1, and M2. The possible metabolic enzymes were marked in the pathway. The findings of this study provide more specific insights into the enantioselective metabolic mechanism of chiral triazole fungicides.

中文翻译：

大鼠对甲氯丁腈的对映选择性分布，降解和代谢产物形成以及大鼠相关代谢基因的转录反应

手性杀真菌剂Myclobutanil（MT）可以在生物体中对映选择性地代谢。在这项工作中，在单剂量（10 mg·kg – ¹体重）暴露于rac -，（+）-或（-）-MT后，确定了MT在大鼠中的相关吸收，分布，代谢和转录反应。随着时间的流逝，在肝脏，肾脏，心脏，肺和睾丸中的对映体分数（EFs）小于0.5，表明（-）-MT在这些组织中的优先富集。此外，暴露于对映纯（+）-MT 6小时后，肝脏和肾脏中的（+）-型转化为（-）-型。两种不同对映体的富集和降解在rac之间有所不同-MT和MT对映体组，表明MT生物蓄积是对映体特异性的。有趣的是，使用rac -MT处理的MT在肝脏中的降解半衰期短于两种MT-对映体处理的MT。原因可能是在三个暴露组中，用rac -MT治疗的肝脏中细胞色素P450 1a2（cyp1a2）和cyp3a2基因的基因表达水平最高。此外，在暴露于rac的肝脏中，发现cyp2e1和cyp3a2基因的表达与rac -MT浓度呈正相关。-公吨。同时，检测到五个手性代谢物，并分离了三种代谢物RH-9090，RH-9089和M2的对映异构体。检测到的（+）-MT代谢物的对映异构体与（-）-MT代谢物的对映异构体完全相反。根据结果，提出了MT在雄性大鼠中的代谢途径，其包括以下五个代谢物：RH-9089，RH-9090，RH-9090硫酸盐，M1和M2。可能的代谢酶标记在该途径中。这项研究的发现为手性三唑类杀菌剂的对映选择性代谢机制提供了更具体的见解。

更新日期：2018-07-18

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