Mycotoxins and the kidney: modes of action for renal tumor formation by ochratoxin A in rodents.
The mycotoxin ochratoxin A (OTA) is a potent renal carcinogen in rodents. OTA is only slowly eliminated due to high affinity to plasma proteins and inefficient biotransformation. A number of mechanisms have been proposed to account for renal tumor formation. DNA adduct formation, mainly based on the( 32)P-postlabeling assay, was postulated as a mode of action (MoA). However, studies using radiolabeled OTA or MS failed to demonstrate formation of OTA-derived DNA-adducts. While some studies have demonstrated generation of oxidative stress by OTA, the oxidative stress response appears to be not very pronounced and therefore may not explain the high potency of OTA in rodents. A number of recent investigations support the hypothesis that OTA causes disruption of mitosis resulting in blocked or asymmetric cell division. This may present an increased risk of aneuploidy acquisition and may play a critical role in OTA-induced tumor formation. The absence of DNA-adducts derived from OTA supports a thresholded MoA, and a tolerable weekly intake (TWI) of 120 ng OTA/kg bw has been derived by the European Food Safety Authority. The estimated intake of OTA in Europe is below this TWI for most of the population.
Mally
Angela
A
Department of Toxicology, University of Würzburg, Germany. mally@toxi.uni-wuerzburg.de
Dekant
Wolfgang
W
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001711:Biotransformation; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007680:Kidney Neoplasms / Q000139:chemically induced*; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D018570:Risk Assessment
D018736:DNA Adducts; D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A; D004247:DNA