JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2020
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IF 4.192
Xiaojing Yang,Yukun Feng,Zhengyu Zhang,Hui Wang,Weiwei Li,Dan Ohtan Wang,Ying Peng,Jiang Zheng
Methyleugenol (ME) is a ubiquitous component in spices and other culinary herbal products. A prevailing theory in ME toxicity is its ability to be metabolically activated by P450 enzymes and sulfotransferases, which initiates sequential reactions of the resulting metabolites with functional biomolecules. The present study aimed at a potential interaction between the reactive metabolites of ME and RNA. Cultured mouse primary hepatocytes were incubated with ME followed by RNA extraction and NaOH and alkaline phosphatase-based RNA hydrolysis. Three adenosine adducts were detected in the hydrolytic mixture by LC–MS/MS. The same adenosine adducts were also detected in hepatic tissues harvested from ME-treated mice. These three adducts were chemically synthesized and structurally characterized by 1H NMR. Additionally, two guanosine adducts and one cytidine adduct were detected in the in vivo samples. These results provided solid evidence that the reactive metabolites of ME attacked RNA, resulting in RNA adduction.
研究领域:
毒理学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
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2022
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IF 5.168
Weiwei Li,Ting Cheng,Tingting Jiang,Mengyue Zhou,Bowen Gong,Guode Zhao,Jing Li,Rong Tan,Xiaojing Yang,Kandarp Joshi,Ying Peng,Maosheng Cheng,Ting Liu,Dan Ohtan Wang,Jiang Zheng
Pyrrolizidine alkaloids (PAs) are among the most significant hepatotoxins widely distributed in plant species. Incidence of liver injuries caused by PAs has been reported worldwide, and the reactive metabolites of PAs are known to play a critical role in causing the hepatotoxicity. To better understand the toxicity-induction mechanisms, we explored the interactions of PA metabolites with cellular RNA molecules, and examined their effects on the biochemical and metabolic properties of hepatic RNAs. After exposure to retrorsine, adduction on adenosine and guanosine were detected in mouse liver microsomal incubations, cultured mouse primary hepatocytes, and mouse liver tissues. NMR analysis showed that the exocyclic amino group participated in the adduction. We found drastically altered properties and metabolism of the adducted RNA such as reverse-transcriptability, translatability, and RNase-susceptibility. In addition, endogenous modification of N 6 -methyladenosine (m6A) was remarkably reduced.
研究领域:
毒理学
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分子生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2024
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IF 5.7
Yan He,Zihao Cheng,Jingyu Zhang,Yu Chen,Guode Zhao,Hong Tang,Yufen Liao,Tingmin Ye,Ying Peng,Weiwei Li,Jiang Zheng
Myristicin (MYR) mainly occurs in nutmeg and belongs to alkoxy-substituted allylbenzenes, a class of potentially toxic natural chemicals. RNA interaction with MYR metabolites in vitro and in vivo has been investigated in order to gain a better understanding of MYR toxicities. We detected two guanosine adducts (GA1 and GA2), two adenosine adducts (AA1 and AA2), and two cytosine adducts (CA1 and CA2) by LC-MS/MS analysis of total RNA extracts from cultured primary mouse hepatocytes and liver tissues of mice after exposure to MYR. An order of nucleoside adductions was found to be GAs > AAs > CAs, and the result of density functional theory calculations was in agreement with that detected by the LC-MS/MS-based approach. In vitro and in vivo studies have shown that MYR was oxidized by cytochrome P450 enzymes to 1′-hydroxyl and 3′-hydroxyl metabolites, which were then sulfated by sulfotransferases (SULTs) to form sulfate esters. The resulting sulfates would react with the nucleosides by SN1 and/or SN2 reactions, resulting in RNA adduction. The modification may alter the biochemical properties of RNA and disrupt RNA functions, perhaps partially contributing to the toxicities of MYR.
研究领域:
毒理学
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药理学
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分子生物学
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分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Xin Wang,Guangyun Ran,Yufen Liao,Bowen Gong,Chutian Wu,Rong Tan,Ying Liu,Shiyu Zhang,Ying Peng,Weiwei Li,Jiang Zheng
Safrole (SFL) is an IARC class 2B carcinogen. To better understand the mechanism involved in SFL toxicity, we explored the potential interactions between SFL metabolites and RNA. Three guanosine adducts (G1-G3), two adenosine adducts (A1-A2), and two cytosine adducts (C1–C2) were detected by LC-MS/MS in mouse liver S9 incubations, cultured mouse primary hepatocytes, and liver tissues of mice after exposure to SFL. These adducts were chemically synthesized, and one of the guanosine adducts was structurally characterized by 1 H-NMR. Studies in vitro and in vivo showed that SFL was oxidized by cytochrome P450 enzymes to the corresponding 1′-hydroxyl metabolite which was further metabolized by sulfotransferases to form allylic sulfate esters. The formed reactive intermediate(s) subsequently reacted with bases of RNA, leading to RNA adduction, which could play a partial role in the toxicities of SFL through the alteration of RNA biochemical properties and interruption of RNA functions.
研究领域:
毒理学
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药理学
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分子生物学
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）