Mutagenicity of Ochratoxin A: Role for a Carbon-Linked C8-Deoxyguanosine Adduct?

作者：Manderville Richard A^*; Wetmore Stacey D^*

来源：Journal of Agricultural and Food Chemistry, 2017, 65(33): 7097-7105.

DOI：10.1021/acs.jafc.6b03897

• ochratoxin A(OTA)
• DNA damage
• DNA addnct
• iDNA structure
• mutagenicity
• DNA replication
• DNA polymerase
• translesion synthesis

Ochratoxin A (OTA) is a fungal toxin that is considered to be a potent kidney carcinogen in rodent models. The toxin produces double strandbreaks and has a propensity for deletions, single base substitutions, And insertions. The toxin reacts covalently with DNA to afford a C8-2'-deoxyguanosine :carbon-linked adduct (QT-dG) as the major lesion in animal tissues. Incorporation of model C-linked C8-aryl-,dGadducts into the G3 site of the Nan sequence demonstrates a tendency to induce base substitutions and deletion mutations in primer extension assays-using model polymerases. The degree of misincorporatibn induced by the C-linked C8-dG adducts correlates with-an ability to adopt the promutagenic syn conformation within the Ncy-I duplex as predicted by molecular dynamics (MD) simulations. MD simulations of the OT-dG adduct within the NarI duplex predict an even greater degree of conformational flexibility, suggesting enhanced in vitro mutagenicity compared to the simpler model C-linked C8-dG adducts. Together these findings support therole, of OT-dG in piothoting OTA-mediated mutagenicity and carcinogenicity in animal studies.

• 出版日期2017-8-23