Comparative metabolism of cyclophosphamide and ifosfamide 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.2010.06.002

Cited by 57 publications

(52 citation statements)

References 42 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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“…Cardiotoxicity is a major problem with people treated with higher dose regimens [13]. In addition, toxicity of cyclophosphamide was report in liver [14]. kidney [15] and testis [16].…”

Section: Introductionmentioning

confidence: 99%

Cyclophosphamide Induced Histologial and Immunohistochemical Alterations in Kidney of Albino Rats: The Ameliorative Effect of Fennel Oil

Sakr¹,

El-messady²

2017

ijSciences

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Cyclophosphamide (CPA) is a nitrogen mustard alkylating agent from the oxazaphosphorine group. It is used as an anticancer, anti-neoplastic agents and immunosuppressive agent widely used in chemotherapy. Fennel oil is traditionally used as a treatment for different diseases. The present work studied the effect of Fennel oil on CPAinduced nephrotoxicity in albino rats. Male albino rats were divided into 4 groups; gp1; control, gp2: Each rat was orally given Fennel oil (1 ml/kg body weight once a week for six weeks), gp3: animals were each orally treated with CPA at a dose of 15mg/kg body weight once a week for six weeks, gp4: CPA plus Fennel oil treated group. The obtained results showed that CPA induced histopathological alterations in the kidney including intertubular leucocytic infiltrations,congestion of blood vessels, degeneration of renal tubules and atrophy of glomeruli. Immunohistochemical observations revealed increase in expression of PCNA, caspase-3 and α -SMA. In addition, creatinine and urea levels increased in sera of treated rats. Treating rats with CPA and fennel oil caused an improvement in the histological structure of the kidney and decreased PCNA, caspase-3 and α-SMA. Moreover, creatinine and urea values were decreased. In conclusion, fennel oil showed ameliorative effect against nephrotoxicity of CPA due to its antioxidant activity.

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“…The quercetin metabolites were initially determined by analyzing the ions in the loadings scatter plot. The identity of metabolites was determined by their mass fragmentation as previously described (8–10). …”

Section: Methodsmentioning

confidence: 99%

Quercetin Inhibits Radiation-Induced Skin Fibrosis

Horton

Chung

et al. 2013

Radiation Research

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Radiation induced fibrosis of the skin is a late toxicity that may result in loss of function due to reduced range of motion and pain. The current study sought to determine if oral delivery of quercetin mitigates radiation-induced cutaneous injury. Female C3H/HeN mice were fed control chow or quercetin-formulated chow (1% by weight). The right hind leg was exposed to 35 Gy of X rays and the mice were followed serially to assess acute toxicity and hind leg extension. Tissue samples were collected for assessment of soluble collagen and tissue cytokines. Human and murine fibroblasts were subjected to clonogenic assays to determine the effects of quercetin on radiation response. Contractility of fibroblasts was assessed with a collagen contraction assay in the presence or absence of quercetin and transforming growth factor-β (TGF-β). Western blotting of proteins involved in fibroblast contractility and TGF-β signaling were performed. Quercetin treatment significantly reduced hind limb contracture, collagen accumulation and expression of TGF-β in irradiated skin. Quercetin had no effect on the radioresponse of fibroblasts or murine tumors, but was capable of reducing the contractility of fibroblasts in response to TGF-β, an effect that correlated with partial stabilization of phosphorylated cofilin. Quercetin is capable of mitigating radiation induced skin fibrosis and should be further explored as a therapy for radiation fibrosis.

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Comparative metabolism of cyclophosphamide and ifosfamide in the mouse using UPLC–ESI-QTOFMS-based metabolomics

Cited by 57 publications

References 42 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

Cyclophosphamide Induced Histologial and Immunohistochemical Alterations in Kidney of Albino Rats: The Ameliorative Effect of Fennel Oil

Quercetin Inhibits Radiation-Induced Skin Fibrosis

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