Identification and quantification of acetyl triethyl citrate metabolites: Insights from in vitro and in vivo analysis

IF 4.2 3区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES

Environmental toxicology and pharmacology Pub Date : 2025-05-28 DOI:10.1016/j.etap.2025.104727

Hyeri Jeon , Daeho Kang , Eun-Ah Park , Kailin Shen , Youngrok Lee , Kijeong Yun , Junho Jeon , Bongjin Moon , Kuynghee Ji , Sungkyoon Kim , Younglim Kho

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引用次数: 0

Abstract

Acetyl triethyl citrate (ATEC), a citric acid ester used as an alternative to phthalate plasticizers, has raised concerns due to reported hepatotoxicity, lipid metabolism disruption, and embryotoxicity. However, data on human metabolites remain limited. This study aimed to identify ATEC metabolites via in vitro and in vivo approaches and establish a method for urinary quantification. In vitro experiments using human liver microsomes (HLM) identified acetyl diethyl citrate (ADEC), triethyl citrate (TEC), and diethyl citrate (DEC). In contrast, human oral administration revealed ADEC, acetyl monoethyl citrate (AMEC), and DEC in urine. ADEC and DEC were synthesized and quantified as reference standards, confirming their biomarker potential. Following oral administration, 37 % of the ATEC dose was excreted in urine as ADEC and DEC within 48 h, indicating their role as major metabolites. These findings provide baseline data for assessing human exposure to ATEC and highlight the need for further investigation of AMEC.

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鉴定和定量的乙酰柠檬酸三乙酯代谢物：从体外和体内分析的见解

乙酰三乙基柠檬酸酯（ATEC）是一种用作邻苯二甲酸酯增塑剂替代品的柠檬酸酯，由于有报道称其具有肝毒性、脂质代谢紊乱和胚胎毒性，因此引起了人们的关注。然而，关于人体代谢物的数据仍然有限。本研究旨在通过体外和体内方法鉴定ATEC代谢物，并建立尿液定量方法。体外实验用人肝微粒体（HLM）鉴定出柠檬酸乙酰二乙酯（ADEC）、柠檬酸三乙酯（TEC）和柠檬酸二乙酯（DEC）。相比之下，人类口服给药在尿液中显示ADEC、乙酰柠檬酸单乙酯（AMEC）和DEC。合成ADEC和DEC作为参比标准物，确定其生物标志物潜力。口服给药后，37 %的ATEC剂量在48 h内以ADEC和DEC的形式从尿液中排出，表明它们是主要代谢物。这些发现为评估人类接触ATEC提供了基线数据，并强调了进一步调查AMEC的必要性。

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来源期刊

Environmental toxicology and pharmacology 医学-毒理学

CiteScore

7.00

自引率

4.70%

发文量

185

审稿时长

34 days

期刊介绍： Environmental Toxicology and Pharmacology publishes the results of studies concerning toxic and pharmacological effects of (human and veterinary) drugs and of environmental contaminants in animals and man. Areas of special interest are: molecular mechanisms of toxicity, biotransformation and toxicokinetics (including toxicokinetic modelling), molecular, biochemical and physiological mechanisms explaining differences in sensitivity between species and individuals, the characterisation of pathophysiological models and mechanisms involved in the development of effects and the identification of biological markers that can be used to study exposure and effects in man and animals. In addition to full length papers, short communications, full-length reviews and mini-reviews, Environmental Toxicology and Pharmacology will publish in depth assessments of special problem areas. The latter publications may exceed the length of a full length paper three to fourfold. A basic requirement is that the assessments are made under the auspices of international groups of leading experts in the fields concerned. The information examined may either consist of data that were already published, or of new data that were obtained within the framework of collaborative research programmes. Provision is also made for the acceptance of minireviews on (classes of) compounds, toxicities or mechanisms, debating recent advances in rapidly developing fields that fall within the scope of the journal.