Abstract:
:Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists such as fenofibrate are used to treat dyslipidemia. Although fenofibrate is considered safe in humans, it is known to cause hepatocarcinogenesis in rodents. To evaluate untargeted metabolic profiling as a tool for gaining insight into the underlying pharmacology and hepatotoxicology, Fischer 344 male rats were dosed with 300 mg/kg/day of fenofibrate for 14 days and the urine and plasma were analyzed on days 2 and 14. A combination of liquid and gas chromatography mass spectrometry returned the profiles of 486 plasma and 932 urinary metabolites. Aside from known pharmacological effects, such as accelerated fatty acid beta-oxidation and reduced plasma cholesterol, new observations on the drug's impact on cellular metabolism were generated. Reductions in TCA cycle intermediates and biochemical evidence of lactic acidosis demonstrated that energy metabolism homeostasis was altered. Perturbation of the glutathione biosynthesis and elevation of oxidative stress markers were observed. Furthermore, tryptophan metabolism was up-regulated, resulting in accumulation of tryptophan metabolites associated with reactive oxygen species generation, suggesting the possibility of oxidative stress as a mechanism of nongenotoxic carcinogenesis. Finally, several metabolites related to liver function, kidney function, cell damage, and cell proliferation were altered by fenofibrate-induced toxicity at this dose.
journal_name
Toxicol Patholjournal_title
Toxicologic pathologyauthors
Ohta T,Masutomi N,Tsutsui N,Sakairi T,Mitchell M,Milburn MV,Ryals JA,Beebe KD,Guo Ldoi
10.1177/0192623309336152subject
Has Abstractpub_date
2009-06-01 00:00:00pages
521-35issue
4eissn
0192-6233issn
1533-1601pii
37/4/521journal_volume
37pub_type
杂志文章abstract::Monocrotaline pyrrole (MCTP) is a highly reactive pneumotoxic metabolite of the pyrrolizidine alkaloid plant toxin monocrotaline. When administered to rats, it causes a delayed and progressive lung injury, vascular remodeling, and pulmonary hypertension. Structural remodeling consists of endothelial cell swelling foll...
journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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journal_title:Toxicologic pathology
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abstract::Overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) has been frequently observed in human hepatocellular carcinoma (HCC),suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we...
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abstract::Absorbable metallic implants have been under investigation for more than a century. Animal and human studies have shown that magnesium (Mg) alloys can be safely used in bioresorbable scaffolds. Several cardiovascular and orthopedic biodegradable metallic devices have recently been approved for use in humans. Bioresorb...
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journal_title:Toxicologic pathology
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abstract::Pentostatin, an adenosine deaminase inhibitor, has been approved for the treatment of refractory hairy cell leukemia. In a preclinical toxicity study, Wistar rats were administered 0, 1, 10, 25, and 50 mg/kg (0, 6, 60, 150, and 300 mg/m2, respectively) pentostatin intravenously once a week for 26 wk (1.5-75-fold above...
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abstract::Phentolamine is a reversible competitive alpha-adrenergic antagonist with similar affinities for alphal and alpha2 receptors. It has a long history of safe clinical use, and was developed as a potential therapy for male erectile dysfunction because of its capacity to increase the arteriolar blood flow to the corpora c...
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abstract::We have previously indicated that the ideal animal tumor model should mimic the human disease. This means that the investigator should be able to ascertain the influence of host factors on the initiation of tumorigenesis, mimic the susceptibility of tumor response based on age and reproductive history, and determine t...
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abstract::Apoptosis is a highly regulated mechanism of cell death. Although apoptosis has a functional role in normal development and tissue homeostasis, aberrant triggering of the process by toxicants may lead to abnormal function or disease. Low level exposures to toxicants that induce apoptosis in kidney may therefore create...
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abstract::Specific regions in the rodent larynx exhibit cellular changes in response to inhaled xenobiotics. These regions include the base of the epiglottis, ventral pouch, and medial surfaces of the vocal processes of the arytenoid cartilages. There are interspecies differences among laboratory rodents in the microscopic anat...
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abstract::Bioabsorbable implants can be advantageous for certain surgical tissue bioengineering applications and implant-assisted tissue repair. They offer the obvious benefits of nonpermanence and eventual restoration of the native tissue's biomechanical and immunological properties, while providing a structural scaffold for h...
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