Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although they are known to be effective antidiabetic agents, little is published about the toxic effects of carnitine palmitoyltransferase-1 (CPT-1) inhibitors, such as etomoxir (ET). These compounds inhibit mitochondrial fatty acid beta-oxidation by irreversibly binding to CPT-1 and preventing entry of long chain fatty acids into the mitochondrial matrix. Treatment of HepG2 cells with 1 mM etomoxir for 6 h caused significant modulations in the expression of several redox-related and cell cycle mRNAs as measured by microarray analysis. Upregulated mRNAs included heme oxygenase 1 (HO1), 8-oxoguanine DNA glycosylase 1 (OGG1), glutathione reductase (GSR), cyclin-dependent kinase inhibitor 1A (CDKN1 [p21(waf1)]) and Mn+ superoxide dismutase precursor (SOD2); while cytochrome P450 1A1 (CYP1A1) and heat shock 70kD protein 1 (HSPA1A) were downregulated. Real time quantitative PCR (RT-PCR) confirmed the significant changes in 4 of 4 mRNAs assayed (CYP1A1, HO1, GSR, CDKN1), and identified 3 additional mRNA changes; 2 redox-related genes, gamma-glutamate-cysteine ligase modifier subunit (GCLM) and thioredoxin reductase (TXNRD1) and 1 DNA replication gene, topoisomerase IIalpha (TOP2A). Temporal changes in selected mRNA levels were examined by RT-PCR over 11 time points from 15 min to 24 h postdosing. CYP1A1 exhibited a 38-fold decrease by 4 h, which rebounded to a 39-fold increase by 20 h. GCLM and TXNRD1 exhibited 13- and 9-fold increases, respectively at 24 h. Etomoxir-induced oxidative stress and impaired mitochondrial energy metabolism were confirmed by a significant decrease in reduced glutathione (GSH), reduced/oxidized glutathione ratio (GSH/GSSG), mitochondrial membrane potential (MMP), and ATP levels, and by concurrent increase in oxidized glutathione (GSSG) and superoxide generation. This is the first report of oxidative stress caused by etomoxir.
 ...
PMID:Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. 1207 14

Mitochondria are essential cellular organelles that participate in important cellular processes, including bioenergetics, metabolism, and signaling. Recent functional and proteomic studies have revealed the remarkable complexity of mitochondrial protein organization. Mitochondrial protein machineries with diverse functions such as protein translocation, respiration, metabolite transport, protein quality control and the control of membrane architecture interact with each other in dynamic networks. The goal of this study was to identify protein expression changes in a human cardiomyocyte cell line treated with several mitochondrial toxicants which inhibit mitochondrial membrane potential (MMP) and mitochondrial respiration. AC16 human cardiomyocyte cells were treated with carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP), dinoterb, picoxystrobin, pinacyanol, and triclocarban for 18 h around the IC50 values generated from MMP assay. The samples were harvested and labeled with tandem mass tags with different mass isotopes. Peptide assignment was performed in Proteome Discoverer. Each dataset was analyzed in Ingenuity Pathway Analysis (IPA). In the proteomic profile, these compounds showed dysregulation of a group of mitochondrial proteins (e.g., NDUA, NDUB, BCS1, CYB5B, and SDHF2), as well as proteins involved in lipid metabolism (e.g., CPT, MECR, and LPGAT1), cytoskeleton protein changes (e.g., CROCC, LAMC3, FBLN1, and FMN2) and stress response (e.g., IKBKG, IKBB, SYVN1, SOD2, and CPIN1). Proteomic data from the current study provides key insights into chemical induced cellular pathway dysregulation, supporting the use of proteomic profiling as a sensitive method to further explore molecular functions and disease pathogenesis upon exposure to environmental chemicals.
 ...
PMID:Quantitative Proteomic Profiling of Mitochondrial Toxicants in a Human Cardiomyocyte Cell Line. 3273 41