Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases

Wang, Xin; Ran, Guangyun; Liao, Yufen; Gong, Bowen; Wu, Chutian; Tan, Rong; Liu, Ying; Zhang, Shiyu; Peng, Ying; Li, Weiwei; Zheng, Jiang

doi:10.1016/j.fct.2023.113688

Cited by 3 publications

(10 citation statements)

References 25 publications

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“…Unfortunately, the detection of AA1 and AA2 was not reproducible, which made it extremely difficult to quantify the particular adducts. Our early studies showed that the reactive intermediates derived from methyleugenol adducted guanosine (two GAs), adenosine (three AAs), and cytidine (CA) of RNAs, and similar adduction selectivity was observed for the reactive intermediates derived from safrole . The present study revealed that the reactive intermediates derived from MYR modified guanosine, adenosine, and cytidine of RNAs (Figure C,D and S4D).…”

Section: Discussionsupporting

confidence: 76%

“…Our early studies showed that the reactive intermediates derived from methyleugenol adducted guanosine (two GAs), adenosine (three AAs), and cytidine (CA) of RNAs, 26 and similar adduction selectivity was observed for the reactive intermediates derived from safrole. 30 The present study revealed that the reactive intermediates derived from MYR modified guanosine, adenosine, and cytidine of RNAs (Figure 1C,D and S4D). The selectivity for attacking the nucleosides by the reactive metabolites of the three alkenylbenzene derivatives is probably similar in cultured hepatocytes.…”

Section: ■ Discussionmentioning

confidence: 50%

“…The resultant electrophilic species react with nucleophilic sites of biological macromolecules such as DNA, and the biomolecule adduction disturbs the corresponding biological functions, leading to genotoxicity. ,− 1′-Hydroxy metabolite of MYR (M5, Scheme ) was reported to be more cytotoxic than MYR itself . The reactive metabolites of methyleugenol and safrole interact covalently with RNA previously. , With reactive metabolites of MYR, we evaluated the risk of RNA adduction. Although MYR is an alkenylbenzene derivative, the potential for metabolic activation of MYR and the reactivity of reactive metabolites, along with the stability of the resulting RNA adducts, may differ from one another.…”

Section: Discussionmentioning

confidence: 99%

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RNA Adduction Resulting from the Metabolic Activation of Myristicin by P450 Enzymes and Sulfotransferases

He,

Cheng,

Zhang

et al. 2024

J. Agric. Food Chem.

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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 S N 1 and/or S N 2 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.

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Section: Discussionsupporting

confidence: 76%

Section: ■ Discussionmentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

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RNA Adduction Resulting from the Metabolic Activation of Myristicin by P450 Enzymes and Sulfotransferases

He,

Cheng,

Zhang

et al. 2024

J. Agric. Food Chem.

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“…The formation of RNA adducts can have various effects on cellular functions, leading to genotoxicity. Wang et al [73] explored the potentially toxic effects of SFO and its metabolites on RNA. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify the RNA adducts formed in the mouse liver S9 fraction, primary liver cells, and liver tissues following SFO exposure.…”

Section: Genetic Toxicity and Carcinogenic Mechanism Of Arrmentioning

confidence: 99%

Research progress on the toxicity of Asari Radix et Rhizoma

Li,

Chen,

Duan

et al. 2024

Acupuncture and Herbal Medicine

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Asari Radix et Rhizoma (ARR), also known as Xixin, has been broadly used as a traditional herbal medicine in East Asia and is an important component of classic prescriptions, including mahuang fuzi xixin decoction. It was initially classified as a “top grade” herb in ancient Chinese Pharmacopeia, Shennong’s Materia Medica. Volatile oils, lignans, fatty acids, flavonoids, and nitrogen-containing compounds are the main ARR components. Previous pharmacological studies have shown that ARR exerts beneficial effects in humans for treating headaches, toothaches, and several inflammatory diseases by dispelling wind and cold, alleviating pain, and eliminating phlegm. However, “the dosage of ARR should not exceed one coin (approximately 3.75 grams)”, as stated in Shizhen Li’s Compendium of Materia, emphasized the considerable ARR toxicity and significantly constrained its clinical application. This review aimed to consolidate recent advancements in the understanding of the toxic ARR components. Additionally, we provide an overview of the hepatotoxicity, genotoxicity, neurotoxicity, and pulmonary toxicity of ARR and discuss the underlying molecular mechanisms. This study reviews the limitations of current studies and enhances our understanding of the toxic effects of ARR from the perspective of its toxic components and mechanisms, thereby providing a theoretical basis for the rational clinical practice of ARR-based medications.

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“…Safrole, myristicin, and ME have been observed to form DNA adducts in vitro and in vivo following metabolic activation [76] . RNA adduction caused by safrole and ME has also been found [77,78] . Urinary ME-deoxyadenosine adducts are potential biomarkers of ME exposure [79] .…”

Section: Metabolic Activation Of Natural Products In Tcmmentioning

confidence: 99%

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

Liu,

Wang,

Liu

et al. 2024

Acupuncture and Herbal Medicine

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Ensuring the safety of traditional Chinese medicines (TCM) has perennially presented a universal challenge in the healthcare realm. Meticulous investigations into the toxicological intricacies of natural products are of paramount significance, particularly regarding the metabolic transformation of these substances and the subsequent generation of reactive intermediates. This biochemical process underlies the genesis of diverse toxic manifestations, including hepatotoxicity, nephrotoxicity, pulmonary toxicity, and genotoxicity. Compounds sorted within TCM, including pyrrolizidine alkaloids, anthraquinones, furanoterpenoids, alkenylbenzenes, bisbenzylisoquinoline alkaloids, flavonoids, and methylenedioxyphenyl derivatives, evince a spectrum of deleterious mechanisms upon metabolic activation. This review provides a comprehensive delineation of the pathways through which these compounds induce toxicity via metabolic activation. This review emphasizes the chemical mechanisms involved in the metabolic activation of natural products that may trigger a toxic cascade, rather than a superficial phenomenon. Furthermore, this study enriches the extant literature by delving into advancements in elucidating the mechanisms of toxicity engendered by metabolic activation. In conclusion, this review highlights the importance of scrutinizing the mechanisms of toxicity and provides insights into the judicious and safe use of TCM.

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Formation of RNA adducts resulting from metabolic activation of spice ingredient safrole mediated by P450 enzymes and sulfotransferases

Cited by 3 publications

References 25 publications

RNA Adduction Resulting from the Metabolic Activation of Myristicin by P450 Enzymes and Sulfotransferases

RNA Adduction Resulting from the Metabolic Activation of Myristicin by P450 Enzymes and Sulfotransferases

Research progress on the toxicity of Asari Radix et Rhizoma

Chemical nature of metabolic activation of natural products in traditional Chinese medicines possibly associated with toxicities

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