Effect of ochratoxin A on redox-regulated transcription factors, antioxidant enzymes and glutathione-S-transferase in cultured kidney tubulus cells.
Ochratoxin A (OTA), a mycotoxin mostly produced by Aspergillus ochraceus and Penicillium verrucosum, is a worldwide contaminant of food and feedstuff. OTA is nephrotoxic and a renal carcinogen in rodents. The underlying molecular and cellular mechanisms by which OTA exhibits its toxicity have yet not been fully clarified. In the present study the effects of ochratoxin A on the activity of redox-regulated transcription factors, antioxidant enzymes, as well as glutathione-S-transferase (GST) have been studied in cultured kidney tubulus cells (LLC-PK1). Confluent LLC-PK1 cells were incubated with increasing concentrations of OTA for 24h. OTA decreased SOD activity and enhanced intracellular levels of reactive oxygen species (ROS) as measured by flow cytometry. Furthermore OTA resulted in a down-regulation of GST mRNA and activity levels. Lower GST levels were accompanied by a decreased transactivation of activator protein-1 (AP-1) and NF-E2-related factor-2 (Nrf2), which mediate GST gene transcription. Present data indicate that enhanced ROS production and an impairment of GST activity, possibly due to an AP-1 and Nrf2 dependent signal transduction pathway, may be centrally involved in OTA induced nephrotoxicity.
Boesch-Saadatmandi
C
C
Institute of Human Nutrition and Food Science, Christian-Albrechts-University Kiel, Herrman-Rodewald-Strasse 6, 24118 Kiel, Germany.
Loboda
A
A
Jozkowicz
A
A
Huebbe
P
P
Blank
R
R
Wolffram
S
S
Dulak
J
J
Rimbach
G
G
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018374:LLC-PK1 Cells; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D009793:Ochratoxins / Q000633:toxicity*; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013552:Swine; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism*
D000975:Antioxidants; D002273:Carcinogens; D051267:NF-E2-Related Factor 2; D009793:Ochratoxins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D014157:Transcription Factors; C025589:ochratoxin A; D005982:Glutathione Transferase