A comprehensive understanding of thioTEPA metabolism in the mouse using UPLC–ESI-QTOFMS-based metabolomics

Li, Fēi; Patterson, Andrew D.; Höfer, Constance C.; Krausz, Kristopher W.; Gonzalez, Frank J.; Idle, Jeffrey R.

doi:10.1016/j.bcp.2011.01.024

Cited by 32 publications

(24 citation statements)

References 26 publications

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“…Recent studies have demonstrated the power of mass spectrometry-based metabolomics to profi le metabolic pathways to reveal the mechanism of action of nuclear receptors and the metabolic fate of drugs (9)(10)(11)(12). Metabolomics has revealed the downregulated tryptophan-nicotinamide pathways following Wy-14,643 treatment ( 9 ) and the decreased excretion of carnitine-conjugated metabolites by fenofi brate treatment in humans ( 13 ).…”

Section: Identifi Cation and Quantitation Of Urinary And Serum Metabomentioning

confidence: 99%

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

Patterson

Krausz

et al. 2012

Journal of Lipid Research

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Peroxisome proliferator-activated receptor ␣ (PPAR␣) is a nuclear hormone receptor regulating genes involved in lipid homeostasis, including fatty acid transport and catabolism, lipoprotein metabolism, glucose homeostasis, and infl ammation ( 1, 2 ). Recent studies have suggested a role for PPAR␣ in bile acid biosynthesis. A previous study reported that the expression level of cholesterol 7 ␣ -hydroxylase (Cyp7a1) and 8 ␤ -hydroxylase (Cyp8b1) was upregulated in wild-type mice during [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio] acetic acid (Wy-14,643) treatment and fasting conditions; this effect was diminished in Ppara -null mice, thus revealing the involvement of PPAR␣ ( 3 ). Another study found that both human CYP7A1 and mouse Cyp7a1 promoters were stimulated by fatty acids and Wy-14,643 treatment ( 4 ). These studies provided compelling evidence that PPAR␣ can positively regulate bile acid biosynthesis. In contrast to the above observations, it Abstract Peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) is a nuclear receptor that regulates fatty acid transport and metabolism. Previous studies revealed that PPAR ␣ can affect bile acid metabolism; however, the mechanism by which PPAR ␣ regulates bile acid homeostasis is not understood. In this study, an ultraperformance liquid chromatography coupled with electrospray ionization qua dru pole time-of-fl ight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics approach was used to profi le metabolites in urine, serum, and bile of wild-type and Ppara -null mice following cholic acid (CA) dietary challenge. Metabolomic analysis showed that the levels of several serum bile acids, such as CA (25-fold) and taurocholic acid (16-fold), were signifi cantly increased in CA-treated Ppara -null mice compared with CA-treated wild-type mice. Phospholipid homeostasis, as revealed by decreased serum lysophos phati dylcholine (LPC) 16:0 (1.6-fold) and LPC 18:0 (1.6-fold), and corticosterone metabolism noted by increased urinary excretion of 11 ␤ -hydroxy-3,20-dioxopregn-4-en-21-oic acid (20-fold) and 11 ␤ ,20 ␣ -dihydroxy-3-oxo-pregn-4-en-21-oic acid (3.6-fold), were disrupted in CA-treated Ppara -null mice. The hepatic levels of mRNA encoding transporters Abcb11, Abcb4, Abca1, Abcg5, and Abcg8 were diminished in Pparanull mice, leading to the accumulation of bile acids in the liver during the CA challenge. These observations revealed that PPAR ␣ is an essential regulator of bile acid biosynthesis, transport, and secretion.

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Section: Identifi Cation and Quantitation Of Urinary And Serum Metabomentioning

confidence: 99%

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

Patterson

Krausz

et al. 2012

Journal of Lipid Research

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“…Metabolomics has been evolving as an important tool to study drug metabolism, and has been applied in the study of several drugs, such as N , N ′, N ″-triethylenethiophosphoramide (ThioTEPA) [14] and arecoline [15]. Compared with traditional metabolite identification methods, metabolomics can yield the full spectrum of metabolites, even those with relatively low abundance, which facilitates the elucidation of novel metabolic pathways [16].…”

Section: Introductionmentioning

confidence: 99%

Metabolic profiling of praziquantel enantiomers

Wang

Fang

Zheng

et al. 2014

Biochemical Pharmacology

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Praziquantel (PZQ), prescribed as a racemic mixture, is the most readily available drug to treat schistosomiasis. In the present study, ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS) based metabolomics was employed to decipher the metabolic pathways and enantioselective metabolic differences of PZQ. Many phase I and four new phase II metabolites were found in urine and feces samples of mice 24h after dosing indicating that the major metabolic reaction encompassed oxidation, dehydrogenation, and glucuronidation. Differences in the formation of all these metabolites were observed between (R)-PZQ and (S)-PZQ. In an in vitro phase I incubation system, the major involvement of CYP3A, CYP2C9, and CYP2C19 in the metabolism of PZQ, and CYP3A, CYP2C9, and CYP2C19 exhibited different catalytic activity towards the PZQ enantiomers. Apparent Km and Vmax differences were observed in the catalytic formation of three mono-oxidized metabolites by CYP2C9 and CYP3A4 further supporting the metabolic differences for PZQ enantiomers. Molecular docking showed that chirality resulted in differences in location and conformation, which likely accounts for the metabolic differences. In conclusion, in silico, in vitro, and in vivo methods revealed the enantioselective metabolic profile of praziquantel.

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“…19–21 However, not to be overlooked, the use of conventional approaches including radiolabeled tracers 22 as well as making use of naturally occurring isotopes, such as 37 Cl, have been instrumental in helping to detect and identify drug metabolites. 5, 6 In this report, we hypothesized that stable isotope- and mass spectrometry-based metabolomics may simultaneously facilitate a better understanding of both the drug metabolism route as well as to identify endogenous biomarkers of drug action (Figure 1). To accomplish this, ultraperformance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based metabolomics combined with multivariate data analysis (MDA) was employed to analyze the metabolites generated from tempol and deuterated tempol and the impact of tempol on endogenous metabolism.…”

Section: Introductionmentioning

confidence: 99%

Stable Isotope- and Mass Spectrometry-based Metabolomics as Tools in Drug Metabolism: A Study Expanding Tempol Pharmacology

Pang

Krausz

et al. 2013

J. Proteome Res.

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The application of mass spectrometry-based metabolomics in the field of drug metabolism has yielded important insights not only into the metabolic routes of drugs but has provided unbiased, global perspectives of the endogenous metabolome that can be useful for identifying biomarkers associated with mechanism of action, efficacy, and toxicity. In this report, a stable isotope- and mass spectrometry-based metabolomics approach that captures both drug metabolism and changes in the endogenous metabolome in a single experiment is described. Here the antioxidant drug tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) was chosen because its mechanism of action is not completely understood and its metabolic fate has not been studied extensively. Furthermore, its small size (MW = 172.2) and chemical composition (C9H18NO2) makes it challenging to distinguish from endogenous metabolites. In this study, mice were dosed with tempol or deuterated tempol (C9D17HNO2) and their urine profiled using ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Principal component analysis of the urinary metabolomics data generated a Y-shaped scatter plot containing drug metabolites (protonated and deuterated) that were clearly distinct from the endogenous metabolites. Ten tempol drug metabolites, including eight novel metabolites, were identified. Phase II metabolism was the major metabolic pathway of tempol in vivo, including glucuronidation and glucosidation. Urinary endogenous metabolites significantly elevated by tempol treatment included 2,8-dihydroxyquinoline (8.0-fold, P<0.05) and 2,8-dihydroxyquinoline-β-D-glucuronide (6.8-fold, P<0.05). Urinary endogenous metabolites significantly attenuated by tempol treatment including pantothenic acid (1.3-fold, P<0.05) and isobutrylcarnitine (5.3-fold, P<0.01). This study underscores the power of a stable isotope- and mass spectrometry-based metabolomics in expanding the view of drug pharmacology.

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A comprehensive understanding of thioTEPA metabolism in the mouse using UPLC–ESI-QTOFMS-based metabolomics

Cited by 32 publications

References 26 publications

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

Metabolomics reveals an essential role for peroxisome proliferator-activated receptor α in bile acid homeostasis

Metabolic profiling of praziquantel enantiomers

Stable Isotope- and Mass Spectrometry-based Metabolomics as Tools in Drug Metabolism: A Study Expanding Tempol Pharmacology

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