Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases

Liu, Yang; Xin, Lihua; Shi, Junzu; Li, Wei; Tian, Min; Hu, Zixia; Peng, Ying; Zheng, Jiang

doi:10.1021/acs.chemrestox.1c00060

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…68,69 Labetalol forms GSH conjugates after sulfation via phase II enzymes. 70 Fluconazole is reported to exhibit mitochondrial dysfunction 71 and induce reactive oxygen species (ROS) formation. 72 Iproniazid is reported to form an isopropyl radical capable of covalent binding to protein.…”

Section: ■ Discussionmentioning

confidence: 99%

Cyanide Trapping of Iminium Ion Reactive Metabolites: Implications for Clinical Hepatotoxicity

Miao,

Dear,

Beaumont

et al. 2024

Chem. Res. Toxicol.

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Reactive metabolite formation is a major mechanism of hepatotoxicity. Although reactive electrophiles can be soft or hard in nature, screening strategies have generally focused on the use of glutathione trapping assays to screen for soft electrophiles, with many data sets available to support their use. The use of a similar assay for hard electrophiles using cyanide as the trapping agent is far less common, and there is a lack of studies with sufficient supporting data. Using a set of 260 compounds with a defined hepatotoxicity status by the FDA, a comprehensive literature search yielded cyanide trapping data on an unbalanced set of 20 compounds that were all clinically hepatotoxic. Thus, a further set of 19 compounds was selected to generate cyanide trapping data, resulting in a more balanced data set of 39 compounds. Analysis of the data demonstrated that the cyanide trapping assay had high specificity (92%) and a positive predictive value (83%) such that hepatotoxic compounds would be confidently flagged. Structural analysis of the adducts formed revealed artifactual methylated cyanide adducts to also occur, highlighting the importance of full structural identification to confirm the nature of the adduct formed. The assay was demonstrated to add the most value for compounds containing typical structural alerts for hard electrophile formation: half of the severe hepatotoxins with these structural alerts formed cyanide adducts, while none of the severe hepatotoxins with no relevant structural alerts formed adducts. The assay conditions used included cytosolic enzymes (e.g., aldehyde oxidase) and an optimized cyanide concentration to minimize the inhibition of cytochrome P450 enzymes by cyanide. Based on the demonstrated added value of this assay, it is to be initiated for use at GSK as part of the integrated hepatotoxicity strategy, with its performance being reviewed periodically as more data is generated.

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Section: ■ Discussionmentioning

confidence: 99%

Cyanide Trapping of Iminium Ion Reactive Metabolites: Implications for Clinical Hepatotoxicity

Miao,

Dear,

Beaumont

et al. 2024

Chem. Res. Toxicol.

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“…2,6-dichloro-4-nitrophenol is a broad-spectrum inhibitor of sulfotransferases. In hepatocytes, pretreatment with 2,6-dichloro-4-nitrophenol may reduce the hepatotoxicity associated with the application of labetalol hydrochloride ( Yang L. et al, 2021 ). However, whether 2,6-dichloro-4-nitrophenol can be used to treat SSc-PH and its possible interaction pattern with RPS3 still need to be corroborated by more studies.…”

Section: Discussionmentioning

confidence: 99%

A signal recognition particle-related joint model of LASSO regression, SVM-RFE and artificial neural network for the diagnosis of systemic sclerosis-associated pulmonary hypertension

Liang²,

Li³

2022

Front. Genet.

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Background: Systemic sclerosis-associated pulmonary hypertension (SSc-PH) is one of the most common causes of death in patients with systemic sclerosis (SSc). The complexity of SSc-PH and the heterogeneity of clinical features in SSc-PH patients contribute to the difficulty of diagnosis. Therefore, there is a pressing need to develop and optimize models for the diagnosis of SSc-PH. Signal recognition particle (SRP) deficiency has been found to promote the progression of multiple cancers, but the relationship between SRP and SSc-PH has not been explored.Methods: First, we obtained the GSE19617 and GSE33463 datasets from the Gene Expression Omnibus (GEO) database as the training set, GSE22356 as the test set, and the SRP-related gene set from the MSigDB database. Next, we identified differentially expressed SRP-related genes (DE-SRPGs) and performed unsupervised clustering and gene enrichment analyses. Then, we used least absolute shrinkage and selection operator (LASSO) regression and support vector machine-recursive feature elimination (SVM-RFE) to identify SRP-related diagnostic genes (SRP-DGs). We constructed an SRP scoring system and a nomogram model based on the SRP-DGs and established an artificial neural network (ANN) for diagnosis. We used receiver operating characteristic (ROC) curves to identify the SRP-related signature in the training and test sets. Finally, we analyzed immune features, signaling pathways, and drugs associated with SRP and investigated SRP-DGs’ functions using single gene batch correlation analysis-based GSEA.Results: We obtained 30 DE-SRPGs and found that they were enriched in functions and pathways such as “protein targeting to ER,” “cytosolic ribosome,” and “coronavirus disease—COVID-19”. Subsequently, we identified seven SRP-DGs whose expression levels and diagnostic efficacy were validated in the test set. As one signature, the area under the ROC curve (AUC) values for seven SRP-DGs were 0.769 and 1.000 in the training and test sets, respectively. Predictions made using the nomogram model are likely beneficial for SSc-PH patients. The AUC values of the ANN were 0.999 and 0.860 in the training and test sets, respectively. Finally, we discovered that some immune cells and pathways, such as activated dendritic cells, complement activation, and heme metabolism, were significantly associated with SRP-DGs and identified ten drugs targeting SRP-DGs.Conclusion: We constructed a reliable SRP-related ANN model for the diagnosis of SSc-PH and investigated the possible role of SRP in the etiopathogenesis of SSc-PH by bioinformatics methods to provide a basis for precision and personalized medicine.

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“…One is to the antihypertensive α- and β-adrenergic receptor antagonist labetalol ( 159 ) which has been studied in more detail (Scheme ). This drug was shown to be associated with in vitro GSH adduct formation in rat and human hepatocytes and in vivo in rats. For an adrenergic agent, labetalol is used at a rather high dose of 200 mg/day.…”

Section: Drugs That Are Benzylic Alcoholsmentioning

confidence: 99%

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

Claesson¹,

Parkes²

2022

J. Med. Chem.

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Reactive metabolite (RM) formation is widely accepted as playing a pivotal role in causing adverse idiosyncratic drug reactions, with most attention paid to drug-induced liver injury. Mechanisms of RM formation are determined by the drug’s properties in relation to human enzymes transforming the drug. This Perspective focuses on enzymatic oxidation of alkyl groups on aromatics leading to quinone methides and benzylic alcohol sulfates as RMs, a topic that has not received very much attention. Unlike previous overviews, we will include in our Perspective several fulvene-like methides such as 3-methyleneindole. We also speculate that a few older drugs may form non-reported methides of this class. In addition, we report a few guiding DFT calculations of changes in free energy on going from a benzylic alcohol to the corresponding methide. Particularly facile reactions of 2-aminothiazole-5-methanol and 4-aminobenzyl alcohol are noted.

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Metabolic Activation and Cytotoxicity of Labetalol Hydrochloride Mediated by Sulfotransferases

Cited by 11 publications

References 28 publications

Cyanide Trapping of Iminium Ion Reactive Metabolites: Implications for Clinical Hepatotoxicity

Cyanide Trapping of Iminium Ion Reactive Metabolites: Implications for Clinical Hepatotoxicity

A signal recognition particle-related joint model of LASSO regression, SVM-RFE and artificial neural network for the diagnosis of systemic sclerosis-associated pulmonary hypertension

Non-innocuous Consequences of Metabolic Oxidation of Alkyls on Arenes

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