Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.6.5.3 (complex I)
 8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Flutamide (FLU) is an antiandrogen primarily used in the treatment of metastatic prostate cancer. It is an idiosyncratic hepatotoxicant that sometimes results in severe liver toxicity. FLU possesses a nitroaromatic group, which may be a contributor to its mechanism of toxicity. A nitro to cyano analogue of FLU (CYA) was synthesized and used to test this hypothesis in the TGFalpha-transfected mouse hepatocyte cell line (TAMH). MTT cell viability assays and confocal microscopy showed that hepatocytes are more sensitive to cytotoxicity caused by FLU than CYA (LD 50 75 vs 150 microM, respectively). Despite the structural modification, the antiandrogen activity of CYA is comparable to that of FLU. Comparisons of transcriptomic changes caused by FLU with those caused by a panel of known cytotoxicants [acetaminophen, tetrafluoroethylcysteine, diquat, and rotenone (ROT)] indicated that FLU results in a temporal gene expression pattern similar to ROT, a known inhibitor of complex I of the electron transport chain. A subsequent microarray analysis comparing FLU to CYA and ROT revealed many similarities among these three compounds; however, FLU and ROT result in more substantial changes than CYA in the expression of genes associated with oxidative phosphorylation, fatty acid beta-oxidation, antioxidant defense, and cell death pathways. Electron microscopy confirmed that FLU leads to mitochondrial toxicity that has some similarities to the mitochondrial effects of ROT, but the morphologic changes caused by FLU were greater in scope with both intra- and intercellular manifestations. Biochemical studies confirmed that both ROT and FLU deplete cellular ATP levels and inhibit complex I of the electron transport chain to a greater extent than CYA. Thus, as compared to CYA, the nitroaromatic group of FLU enhances cytotoxicity to hepatocytes, likely through mechanisms involving mitochondrial dysfunction and ATP depletion that include complex I inhibition.
 ...
PMID:Comparison of the cytotoxicity of the nitroaromatic drug flutamide to its cyano analogue in the hepatocyte cell line TAMH: evidence for complex I inhibition and mitochondrial dysfunction using toxicogenomic screening. 1770 27

The androgen receptor antagonist, flutamide, is strongly associated with idiosyncratic drug-induced liver injury (DILI). Following administration, flutamide undergoes extensive first-pass metabolism to its primary metabolite, 2-hydroxyflutamide. Flutamide is a known mitochondrial toxicant; however there has been limited investigation into the potential mitochondrial toxicity of 2-hydroxyflutamide and its contribution to flutamide-induced liver injury. In this study we have used the acute glucose or galactose-conditioning of HepG2 cells to compare the mitochondrial toxicity of flutamide, 2-hydroxyflutamide and the structurally-related, non-hepatotoxic androgen receptor antagonist, bicalutamide. Compound-induced changes in mitochondrial oxygen consumption rate were assessed using Seahorse technology. Permeabilization of cells and delivery of specific substrates and inhibitors of the various respiratory complexes provided more detailed information on the origin of mitochondrial perturbations. These analyses were supported by assessment of downstream impacts including changes in cellular NAD(+)/NADH ratio. Bicalutamide was not found to be a mitochondrial toxicant, yet flutamide and 2-hydroxyflutamide significantly reduced basal and maximal respiration. Both flutamide and 2-hydroxyflutamide significantly reduced respiratory complex I-linked respiration, though 2-hydroxyflutamide also significantly decreased complex II and V-linked respiration; liabilities not demonstrated by the parent compound. This study has identified for the first time, the additional mitochondrial liabilities of the major metabolite, 2-hydroxyflutamide compared with its parent drug, flutamide. Given the rapid production of this metabolite upon administration of flutamide, but not bicalutamide, we propose that the additional mitochondrial toxicity of 2-hydroxyflutamide may fundamentally contribute to the idiosyncratic DILI seen in flutamide-treated, but not bicalutamide-treated patients.
 ...
PMID:Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells. 2741 13