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Elucidation of the relationship between evodiamine-induced liver injury and CYP3A4-mediated metabolic activation by UPLC-MS/MS analysis

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Abstract

Evodiamine (EVD), which has been reported to cause liver damage, is the main constituent of Evodia rutaecarpa (Juss.) Benth and may be bioactivated into reactive metabolites mediated by cytochrome P450. However, the relationships between bioactivation and EVD-induced hepatotoxicity remain unknown. In this study, comprehensive hepatotoxicity evaluation was explored, which demonstrated that EVD caused hepatotoxicity in both time- and dose-dependent manners in mice. By application of UPLC-Q/TOF-MS/MS, two GSH conjugates (GM1 and GM2) derived from reactive metabolites of EVD were identified, in microsomal incubation systems exposed to EVD with glutathione (GSH) as trapping agents. CYP3A4 was proved to be the main metabolic enzyme. Correspondingly, the N-acetyl-L-cysteine conjugate derived from the degradation of GM2 was detected in the urine of mice after exposure to EVD. For the first time, the iminoquinone intermediate was found in EVD-pretreated rat bile by the high-resolution MS platform. Pretreatment with ketoconazole protected the animals from hepatotoxicity, decreased the protein expression of cleaved caspase-1 and -3, but increased the area under the serum-concentration-time curve of EVD in blood determined by UPLC-QQQ-MS/MS. Depletion of GSH by buthionine sulfoximine exacerbated EVD-induced hepatotoxicity. These results implicated that the CYP3A4-mediated metabolic activation was responsible for the observed hepatotoxicity induced by EVD.

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Abbreviations

ACN:

Acetonitrile

ALT:

Alanine amino transaminase

AST:

Aspartate amino transaminase

AUC:

Area under the serum-concentration-time curve

BSO:

Buthionine sulfoximine

Caspases:

Cysteinyl aspartate specific proteinases

CLz/F:

Clearance rate

Cmax :

Maximum serum concentration

CON:

Control

DEX:

Dextromethorphan

DIOB:

Diosbulbin B

EC:

Elemental composition

EIs:

Electrophilic reactive metabolites

EPI:

Enhanced product ion

ESI:

Electrospray ionization

EVD:

Evodiamine

GSH:

Glutathione

H&E:

Hematoxylin and eosin

i.p.:

Intraperitoneal

KM:

Kunming mice

KTC:

Ketoconazole

LIM:

Limonin

LLOQ:

Lower limit of quantification

MLM:

Mice liver microsome

MS:

Mass

m/z :

Mass to charge ratio

NAC:

N-Acetyl-L-cysteine

NADPH:

Nicotinamide adenine dinucleotide phosphate

PBS:

Phosphate-buffered saline

ppm:

Parts per million

PVDF:

Polyvinylidene fluoride

QQQ:

Triple quadrupole

Q/TOF:

Quadrupole/time of flight

RLM:

Rat liver microsome

RUT:

Rutaecarpine

SD:

Sprague-Dawley

SDS-PAGE:

Sodium dodecyl sulfate-polyacrylamide gel electrophoresis

t1/2z:

Elimination half-life

Tmax :

Time required to reach maximum serum concentration

UPLC:

Ultra performance liquid chromatography

Vz/F:

Distribution of apparent solvent

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Funding

This work was supported by the National Nature Science Foundation of China (Grant No. 81803615), the Technology Major Project of China “Key New Drug Creation and Manufacturing Program” (Grant No. 2017ZX09301012-001), Tianjin Graduate Research Innovation Project (2022BKY178, 2022SKY224), and TUTCM Graduate Research Innovation Project (YJSKC-20221007, YJSKC-20221034).

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Authors and Affiliations

  1. School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China

    Ting Peng, Jinqiu Rao, Tingting Zhang, Yuan Wang, Na Li, Xinchi Feng, Kai Wang & Feng Qiu

  2. State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China

    Ting Peng, Jinqiu Rao, Tingting Zhang, Yuan Wang, Na Li & Feng Qiu

  3. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of China

    Qing Gao

  4. State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Pharmaceutical Group Co Ltd, Tianjin, 300410, People’s Republic of China

    Zhaohui Song

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  1. Ting Peng
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  2. Jinqiu Rao
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  4. Yuan Wang
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Contributions

Ting Peng: investigation, methodology, data curation, software, writing — original draft. Jinqiu Rao: methodology, visualization, investigation. Tingting zhang: methodology, visualization, investigation. Yuan Wang: visualization, investigation. Na Li: visualization, investigation. Qing Gao: writing, review and editing; formal analysis; data curation. Xinchi Feng: writing — review and editing. Zhaohui Song: writing — review and editing. Kai Wang: project administration, formal analysis, funding acquisition, writing — original draft. Feng Qiu: formal analysis, visualization, funding acquisition, supervision, writing — review and editing. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

Corresponding authors

Correspondence to Kai Wang or Feng Qiu.

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We declare that the study was performed according to the international, national, and institutional rules considering animal experiments, and biodiversity rights.

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Male SD rats were acquired from the Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China, Certificate No. SCXK-2016-0011). Male Kunming (KM) mice were purchased from SPF (Beijing) Biotechnology Co., Ltd. (Beijing, China, Certificate No. SCXK-2019-0010).

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Peng, T., Rao, J., Zhang, T. et al. Elucidation of the relationship between evodiamine-induced liver injury and CYP3A4-mediated metabolic activation by UPLC-MS/MS analysis. Anal Bioanal Chem 415, 5619–5635 (2023). https://doi.org/10.1007/s00216-023-04831-3

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