Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ochratoxin A (OTA), a mycotoxin produced by several Aspergillus and Penicillium species, is a worldwide contaminant of food and feedstuffs. It is nephrotoxic, immunosuppressive and carcinogenic in several animal species. The mechanism by which OTA acts is not fully understood up to now. Here, OTA was evaluated for mutagenicity in the Salmonella typhimurium assay (Ames assay) and in the HPRT assay with V79 hamster fibroblasts. In the bacterial assay using the strains TA 98, TA 100, TA 1535, TA 1538, TA 102 and TA 104, OTA was not mutagenic at a concentration range from 0.01 to 500 micro M in the presence and absence of an external metabolising enzyme system (rat liver S9 enzyme mix). In V79 fibroblasts, cytotoxicity of OTA was estimated with the neutral red uptake assay. An IC(50) of 11.6 micro M was found in the absence and an IC(50) of 6.4 micro M in the presence of S9 mix. In the subsequent HPRT (hypoxanthine-guanine-phosphoribosyl-transferase) assay with V79 cells the negative result of the bacterial assay was confirmed using OTA in concentrations from 0.1 to 100 micro M. In order to obtain converted OTA metabolites from viable, metabolically competent cells, a preincubation of primary cultured rat hepatocytes with 0.016 to 0.8 micro M OTA was performed. The resulting culture medium, which contained OTA metabolites, was tested in both mutagenicity assays. Again, no mutagenic effect was detected either in the bacterial or in the mammalian test assay. In accordance with several literature data, the present results imply that OTA does not act as direct mutagen. Additionally, the OTA metabolites derived from cultured rat hepatocytes or rat liver S9 mix, also, do not have a mutagenic potency in the test systems used.
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PMID:Effects of the mycotoxin ochratoxin A in a bacterial and a mammalian in vitro mutagenicity test system. 1273 45

Ochratoxin A (OTA) is a widespread mycotoxin in food and a powerful nephrocarcinogen in rats. The mutagenicity of OTA has been extensively investigated but with conflicting results, thus leaving open the mechanistic question for OTA carcinogenicity. Here, we examined the mutagenicity of OTA by using well-standardized mutation assays such as the hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay in Chinese hamster V79 cells and the thymidine kinase assay in mouse lymphoma LY5178 cells. OTA-induced HPRT mutations were characterized at the molecular level. In V79 cells, OTA produced a dose- and time-related decrease in cell number as a consequence of the transitory cytostatic effect mediated by G2/M cell cycle arrest. In both mutation assays, OTA was weakly mutagenic and this effect was independent of biotransformation. OTA-induced mutations were characterized by point mutations (48%) and a lack of a detectable reverse-transcription polymerase chain reaction product (52%). The pattern of OTA-induced point mutations was similar to that of spontaneous mutants, suggesting that OTA induced an increase of the endogenous oxidative metabolism but not covalent DNA adducts. Our data support a model where OTA is mutagenic via oxidative DNA damage induction.
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PMID:Ochratoxin A-induced mutagenesis in mammalian cells is consistent with the production of oxidative stress. 1756 56