HEPATOPROTECTIVЕ EFFECT OF THE THOROUGHWAX EXTRACT IN EXPERIMENTAL TETRACYCLINE-INDUCED HEPATITIS

В последние годы возросла распространённость лекарственных поражений печени. В профилактике и лечении таких заболеваний актуальным считают применение препаратов растительного происхождения. Перспективным объектом для разработки таких препаратов является растение володушка золотистая. В ФГБНУ ВИЛАР разработан и стандартизирован сухой экстракт травы володушки золотистой. В составе экстракта содержатся флавоноиды, сапонины, полисахариды, дубильные вещества катехиновой природы. Содержание фенольных соединений в пересчете на рутин составляет не менее 6%. Цель - оценка гепатозащитного действия экстракта володушки при экспериментальном тетрациклиновом гепатите. Методика. Исследовано влияние экстракта володушки (Bupleurum aureum Fisch.) на состояние печени крыс в условиях экспериментального тетрациклинового гепатита в сравнении с известным растительным лекарственным препаратом гепатопротекторного действия Силимаром. Гепатопротекторные и детоксицирующие свойства экстракта володушки оценивали по изменению содержания микросомального белка и цитохрома Р450 в микросомальных фракциях печени экспериментальных групп животных, а также по изменению активности ключевых ферментов системы детоксикации микросом печени, катализирующих ферментативные реакции: цитохрома Р450 и глутатионтрансферазы. Результаты. Установлено, что экстракт володушки в экспериментально-терапевтической дозе (100 мг/кг) обладает статистически значимыми гепатопротекторными и детоксицирующими свойствами, оказывает существенный эффект на активность ферментов микросомальной системы детоксикации (цитохром Р450 и глутатионтрансферазу) в печени крыс. Заключение. Экстракт володушки является перспективным объектом для создания новых высокоэффективных лекарственных средств растительного происхождения для профилактики и лечения лекарственных поражений печени. Prevalence of drug-induced hepatic disorders has greatly increased during recent years, and the use of herbal remedies is considered relevant for their prevention and treatment. A promising object for development of such drugs is thoroughwax (Bupleurum aureum). A dry extract of this herb was developed and standardized at the National Research Institute of Therapeutic and Aromatic Plants. The extract contains flavonoids, saponins, polysaccharides, and tanning substances of the catechine group. The content of phenolic substances is not less than 6% in rutin equivalents. Aim. To study hepatoprotective effects of the thoroughwax (Bupleurum aureum Fisch.) extract in rats with experimental tetracycline-induced hepatitis as compared to a well-known herbal hepatoprotective agent, Silimar. Hepatoprotective and detoxifying properties of the thoroughwax extract were assessed by changes in concentrations of microsomal protein and cytochrome P450 in hepatic microsomal fractions and changes in activities of key enzymes of the hepatic microsomal detoxifying system, which catalyzes enzyme reactions of cytochrome P450 and glutathione transferase. Results. The thoroughwax extract at an experimental therapeutic dose of 100 mg/kg provided significant hepatoprotective and detoxifying effects and induced a strong activation of the microsomal detoxifying enzymes, cytochrome P450 and glutathione transferase, in the rat liver. The thoroughwax extract is promising for development of new, effective herbal drugs for prevention and treatment of drug-induced hepatic disorders.

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Assessment of the Cytochrome P450 (CYP) interaction potential by Sideritis scardica hydroethanolic dry extract illuMind™

10.1055/s-0039-1697298 ◽

2019 ◽

Author(s):

B Feistel ◽

F Heiner ◽

K Appel

Keyword(s):

Cytochrome P450 ◽

Interaction Potential ◽

Dry Extract

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Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report

International Journal of Molecular Sciences ◽

10.3390/ijms22126480 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6480

Author(s):

Céline K. Stäuble ◽

Markus L. Lampert ◽

Thorsten Mikoteit ◽

Martin Hatzinger ◽

Kurt E. Hersberger ◽

...

Keyword(s):

Cytochrome P450 ◽

Case Report ◽

Adverse Drug Reactions ◽

Active Metabolite ◽

Hepatic Metabolism ◽

Cytochrome P450 3A4 ◽

Drug Reactions ◽

Drug Induced ◽

Potential Impact ◽

Intermediate Metabolizer

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

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Proteomic profiling of murine biliary-derived hepatic organoids and their capacity for drug disposition, bioactivation and detoxification

Archives of Toxicology ◽

10.1007/s00204-021-03075-3 ◽

2021 ◽

Author(s):

Lawrence Howell ◽

Rosalind E. Jenkins ◽

Stephen Lynch ◽

Carrie Duckworth ◽

B. Kevin Park ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Metabolism ◽

Rna Polymerase Ii ◽

Liver Tissue ◽

Drug Disposition ◽

Multiple Drug ◽

Proteomic Profiling ◽

Cytochrome P450 3A ◽

Drug Induced

AbstractHepatic organoids are a recent innovation in in vitro modeling. Initial studies suggest that organoids better recapitulate the liver phenotype in vitro compared to pre-existing proliferative cell models. However, their potential for drug metabolism and detoxification remains poorly characterized, and their global proteome has yet to be compared to their tissue of origin. This analysis is urgently needed to determine what gain-of-function this new model may represent for modeling the physiological and toxicological response of the liver to xenobiotics. Global proteomic profiling of undifferentiated and differentiated hepatic murine organoids and donor-matched livers was, therefore, performed to assess both their similarity to liver tissue, and the expression of drug-metabolizing enzymes and transporters. This analysis quantified 4405 proteins across all sample types. Data are available via ProteomeXchange (PXD017986). Differentiation of organoids significantly increased the expression of multiple cytochrome P450, phase II enzymes, liver biomarkers and hepatic transporters. While the final phenotype of differentiated organoids is distinct from liver tissue, the organoids contain multiple drug metabolizing and transporter proteins necessary for liver function and drug metabolism, such as cytochrome P450 3A, glutathione-S-transferase alpha and multidrug resistance protein 1A. Indeed, the differentiated organoids were shown to exhibit increased sensitivity to midazolam (10–1000 µM) and irinotecan (1–100 µM), when compared to the undifferentiated organoids. The predicted reduced activity of HNF4A and a resulting dysregulation of RNA polymerase II may explain the partial differentiation of the organoids. Although further experimentation, optimization and characterization is needed relative to pre-existing models to fully contextualize their use as an in vitro model of drug-induced liver injury, hepatic organoids represent an attractive novel model of the response of the liver to xenobiotics. The current study also highlights the utility of global proteomic analyses for rapid and accurate evaluation of organoid-based test systems.

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