Dataset Information

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography-Mass Spectrometry-Based Metabolomics.

ABSTRACT: Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography-mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as "flags" to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach.

SUBMITTER: Kim JH

PROVIDER: S-EPMC5372636 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography-Mass Spectrometry-Based Metabolomics.

Kim Ju-Hyun JH Choi Won-Gu WG Lee Sangkyu S Lee Hye Suk HS

International journal of molecular sciences 20170313 3

Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography-mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites ...[more]

PMID: 28335386

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Project description:Both obesity and the metabolic syndrome are risk factors for type 2 diabetes and cardiovascular disease. Identification of novel biomarkers are needed to distinguish metabolic syndrome from equally obese individuals in order to direct them to early interventions that reduce their risk of developing further health problems. We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established metabolic syndrome criteria (i.e. elevated waist circumference, hypertension, elevated fasting glucose, elevated triglycerides, and low high-density lipoprotein cholesterol) in plasma samples from obese men ( n = 29; BMI = 35.5 ± 5.2 kg/m2) and women ( n = 40; 34.9 ± 6.7 kg/m2), of which 26 met the criteria for metabolic syndrome (17 men and 9 women). Compared to obese individuals without metabolic syndrome, univariate statistical analysis and partial least squares discriminant analysis showed that a specific group of metabolites from multiple metabolic pathways (i.e. purine metabolism, valine, leucine and isoleucine degradation, and tryptophan metabolism) were associated with the presence of metabolic syndrome. Receiver operating characteristic curves generated based on the PLS-DA models showed excellent areas under the curve (0.85 and 0.96, for metabolites only model and enhanced metabolites model, respectively), high specificities (0.86 and 0.93), and good sensitivities (0.71 and 0.91). Moreover, principal component analysis revealed that metabolic profiles can be used to further differentiate metabolic syndrome with 3 versus 4-5 metabolic syndrome criteria. Collectively, these findings support targeted metabolomics approaches to distinguish metabolic syndrome from obesity alone, and to stratify metabolic syndrome status based on the number of criteria met. Impact statement We utilized mass spectrometry-based targeted metabolic profiling of 221 metabolites to evaluate the associations between metabolite profiles and established MetS criteria. To our best knowledge, the findings of this study provide the first evidence that metabolic profiles can be used to differentiate participants with MetS from similarly obese individuals who do not meet established criteria of MetS. Furthermore, the study demonstrated that within MetS participants, their unique metabolic profiles correlated to the number of criteria used for MetS determination. Taken together, this metabolic profiling approach can potentially serve as a novel tool for MetS detection and monitoring, and provide useful metabolic information for future interventions targeting obesity and MetS.

Dataset Information

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography-Mass Spectrometry-Based Metabolomics.

Publications

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography-Mass Spectrometry-Based Metabolomics.

Similar Datasets

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