Document Detail

Structure-Activity Relationships Imply Different Mechanisms of Action for Ochratoxin A-Mediated Cytotoxicity and Genotoxicity.
MedLine Citation:
PMID:  22126095     Owner:  NLM     Status:  Publisher    
Ochratoxin A (OTA) is a fungal toxin that is classified as a possible human carcinogen based on sufficient evidence for carcinogenicity in animal studies. The toxin is known to promote oxidative DNA damage through production of reactive oxygen species (ROS). The toxin also generates covalent DNA adducts and it has been difficult to separate the biological effects caused by DNA adduction from that of ROS generation. In the current study we have derived structure activity relationships (SAR) for the role of the C5 substituent of OTA (C5-X = Cl) by first comparing the ability of OTA, OTBr (C5-X = Br), OTB (C5-X = H) and OTHQ (C5-X = OH) to photochemically react with GSH and 2'-deoxyguanosine (dG). OTA, OTBr and OTHQ react covalently with GSH and dG following photoirradiation, while the nonchlorinated OTB does not react photochemically with GSH and dG. These findings correlate with their ability to generate covalent DNA adducts (direct genotoxicity) in human bronchial epithelial cells (WI26) and human kidney (HK2) cells, as evidenced by the 32P-postlabeling technique. OTB lacks direct genotoxicity, while OTA, OTBr and OTHQ act as direct genotoxins. In contrast, their cytotoxicity in opossum kidney epithelial cells (OP) and WI26 cells did not show a correlation with photoreactivity. In OK and WI26 cells OTA, OTBr and OTB are cytotoxic, while the hydroquinone OTHQ failed to exhibit cytotoxicity. Overall, our data shows that the C5-Cl atom of OTA is critical for direct genotoxicity, but plays a lesser role in OTA-mediated cytotoxicity. These SAR suggest different mechanisms of action (MOA) for OTA genotoxicity and cytotoxicity, and are consistent with recent findings showing OTA mutagenicity to stem from direct genotoxicity, while cytotoxicity is derived from ROS generation.
Kheira Hadjeba-Medjdoub; Mariana Tozlovanu; Annie Pfohl-Leszkowicz; Christine Frenette; Robert Paugh; Richard Arnold Manderville
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-11-29
Journal Detail:
Title:  Chemical research in toxicology     Volume:  -     ISSN:  1520-5010     ISO Abbreviation:  -     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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