Metabolic Activation of -Anethole Plays a Role in Hepatic Cytotoxicity in Mice.

-Anethole (1-methoxy-4-[1()-propenyl]benzene, tAT) is the main ingredient in the essential oil extracted from star anise fruits. The double bonds in the side chain of tAT are a type of alert structure that can be metabolized into epoxides possibly causing liver damage. This work investigated and identified the reactive metabolites of tAT that are chemically reactive to biothiols, such glutathione (GSH), -acetyl-l-cysteine (NAC), and cysteine residues of proteins.

Metabolic Activation of Stiripentol Correlates with Cytotoxicity.

Stiripentol (SRP) is an antiepileptic agent utilized in managing seizures related to Dravet syndrome. Long-term safety studies have highlighted significant adverse effects in patients including drowsiness, reduced appetite, ataxia, and elevated levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). The present study aimed at identifying the reactive metabolite of SRP and defining the potential correlation between its cytotoxicity and metabolic activation.

Mechanistic Understanding of Differences in Cytotoxicity Induced by Food Additives Methyleugenol and Methylisoeugenol.

Methyleugenol (ME) has been classified as a "group 2B carcinogen" by IARC. Its positional isomer methylisoeugenol (MIE) has been considered to be of "generally recognized as safe'' status by FDA. ME was more cytotoxic than MIE in cultured mouse primary hepatocytes.

Metabolic activation and hepatic cytotoxicity of osthole mediated by cytochrome P450 enzymes.

Osthole (OST), a coumarin derivative, is one of the major components of Cnidium monnieri (L.) Cussion. OST was reported to induce apoptosis in hepatocytes.

Metabolic Activation and Cytotoxicity of Donepezil Induced by CYP3A4.

Donepezil (DNP) is a selective cholinesterase inhibitor widely used for the therapy of Alzheimer's disease. Instances of liver injury correlated with DNP treatment have been reported, yet the underlying hepatotoxic mechanism remains to be elucidated. This study aimed to explore the contribution of metabolic activation to the hepatotoxicity of DNP.

Enhancing Aromaticity of Alkenylbenzenes May Decrease Their Metabolic Activation and Reduce Their Potential Cytotoxicity: Lessons Learnt from the Investigation of Myristicin and Elemicin.

Metabolic activation studies of lead compounds are a crucial step in drug development and offer a key consideration during rational drug design. Myristicin (MRS) and elemicin (ELM), natural products belonging to alkenylbenzenes, share the backbone of 1-allyl-3-methoxybenzene. The backbone fuses with a methylenedioxy five-membered ring in MRS, while ELM is connected with two adjacent methoxy groups.

Correlation of Vanillin-Induced Cytotoxicity with CYP3A-Mediated Metabolic Activation.

Vanillin (VAN) is a common flavoring agent that can cause liver damage when ingested in large amounts. Nevertheless, the precise processes responsible for its toxicity remain obscure. The present research aimed to examine the metabolic activation of VAN and establish a potential correlation between its reactive metabolites and its cytotoxicity.

Mass Spectrometry Imaging of Amino Acids Enabled by Quaternized Pyridinium Salt MALDI Probe.

The distribution of small biomolecules, particularly amino acids (AAs), differs between normal cells and cancer cells. Imaging this distribution is crucial for gaining a deeper understanding of their physiological and pathological significance. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) provides accurate visualization information.

Metabolic Activation and Cytotoxicity of Gramine Mediated by CYP3A in Rats.

Gramine (GRM), which occurs in Gramineae plants, has been developed to be a biological insecticide. Exposure to GRM was reported to induce elevations of serum ALT and AST in rats, but the mechanisms of the observed hepatotoxicity have not been elucidated. The present study aimed to identify reactive metabolites that potentially participate in the toxicity.

Chelerythrine Chloride is an Affinity-Labeling Inactivator of CYP3A4 by Modification of Cysteine239.

Chelerythrine chloride (CHE) is a quaternary benzo[]phenanthridine alkaloid with an iminium group that was found to cause time- and concentration-dependent inhibition of CYP3A4. The loss of CYP3A4 activity was independent of NADPH. CYP3A4 competitive inhibitor ketoconazole and nucleophile -acetylcysteine (NAC) slowed the inactivation.

Mechanism-Based Inactivation of CYP2D6 by Phellopterin and Related Drug-Drug Interaction with Metoprolol.

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners.

Glutathione conjugation and protein modification resulting from metabolic activation of pesticide metalaxyl in vitro and in vivo.

Metalaxyl (MTL), a germicidal agent, is widely used in agriculture. Due to the biological amplification effect, MTL entering the ecological environment would result in a threat to human health through the food chain. MTL is reportedly accumulated in liver.

Metabolic activation and cytotoxicity of metaxalone mediated by cytochrome P450 enzymes and sulfotransferases.

Metaxalone (MTX) is a central nervous system (CNS) depressant used for the treatment of acute skeletal muscle pain. Several cases of fatal overdose deaths in the clinical use of MTX, along with the presence of ischemic hepatitis in deceased patients, have been documented. The present study aimed to investigate the metabolic activation of MTX and to define the possible correlation between the metabolic activation and cytotoxicity of MTX.

Metabolic activation and cytotoxicity of 4-methylquinoline mediated by CYP3A4 and sulfotransferases in rats.

4-Methylquinoline (4-MQ) is a quinoline derivative widely present in groundwater and soil and has been reported to be genotoxic. The mechanisms of the toxic action remain unknown. This study aimed to elucidate the metabolic activation of 4-MQ and to determine the possible role of reactive metabolites in 4-MQ-induced liver injury in rats.

Difference in hepatotoxicity of furan-containing components in cortex dictamni correlates the efficiency of their metabolic activation.

Background: Cortex Dictamni (CD) has been associated with an increased risk of liver injury, which may be attributable to the metabolic activation of its furan-containing components (FCC). However, the hepatotoxic potencies of these FCCs and the mechanisms behind the differences in their toxicity intensity remain unknown.

Methods: The constituents of CD extract were determined by LC-MS/MS.

Reduction of emodin-8-O-ß-D-glucoside content participates in processing-based detoxification of polygoni multiflori radix.

Background: The occurrence of severe liver injury by the herbal medicine Polygoni Multiflori Radix (PMR) has drawn significant attention. The fact that processing attenuates PMR-induced hepatotoxicity has been well accepted, but the mechanisms are still ambiguous.

Purpose: This study aimed to illuminate the mechanism of processing-based attenuation of PMR hepatotoxicity.

In Vitro and In Vivo Metabolic Activation of Tolterodine Mediated by CYP3A.

Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity.

Configurational Alteration Results in Change in Hepatotoxicity of Asarone.

α-Asarone (αA) and β-asarone (βA) are often used as flavoring agents for alcoholic beverages and food supplements. They possess a double bond in the side chain with different configurations. Double bonds are a class of alert chemical group, due to their metabolic epoxidation to the corresponding epoxides eliciting liver injury.

2,3,5,4'-Tetrahydroxy stilbene-2-Ο-β-D-glucoside, a mechanism-based inactivator of CYP2C19 and CYP3A4, potentiates hepatic protein adduction and hepatotoxicity induced by emodin in vivo.

2,3,5,4'-Tetrahydroxy stilbene-2-Ο-β-D-glucoside (TSG) and emodin (EMD) are two main components of Polygonum multiflorum Thunb. (PMT). Its root is widely used as herbal medicine and supplement.

Hepatic RNA adduction derived from metabolic activation of retrorsine in vitro and in vivo.

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.

Metabolic Activation of Perampanel Mediated by CYP1A2.

Perampanel (PRP), a noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonist with high selectivity, has been used as a new adjuvant for the treatment of fractional seizures with or without primary generalized tonic-clonic seizures and secondary generalized seizures in epilepsy patients over the age of 12. Adverse events such as liver injury have been reported during the clinical application of PRP. The purpose of the study is to explore the and metabolic activation of PRP.

Tofacitinib Is a Mechanism-Based Inactivator of Cytochrome P450 3A4.

Tofacitinib (TFT) is an oral JAK inhibitor which has been approved for the treatment of moderately and severely active rheumatoid arthritis. TFT was found to show concentration-, time-, and NADPH-dependent inhibition of CYP3A4, and irreversibility of the inactivation was also observed. Incubation (40 min, 37 °C) of recombinant CYP3A4 with TFT at 200 μM resulted in >70% loss of CYP3A4 activity.

Studies on hepatotoxicity and toxicokinetics of colchicine.

Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use.