The C8-2'-deoxyguanosine adduct of 2-amino-3-methylimidazo[1,2-d]naphthalene, a carbocyclic analogue of the potent mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, is a block to replication in vitro

Chem Res Toxicol. 2010 Jun 21;23(6):1076-88. doi: 10.1021/tx100053n.


2-Amino-3-methylimidazo[1,2-d]naphthalene (cIQ) is a carbocyclic analogue of the dietary carcinogen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in which a naphthalene ring system replaces the quinoline unit of IQ. The activity of cIQ in Ames Salmonella typhimurium tester strain TA98 is known to be 4-5 orders of magnitude lower than IQ. cIQ undergoes efficient bioactivation with rat liver microsomes. The C8-dGuo adduct was formed when calf thymus DNA was treated with the N-hydroxy-cIQ metabolite and either acetic anhydride or extracts from cells that overexpress N-acetyl transferase (NAT). These studies indicate that bioactivation, the stability of the N-hydroxylamine ester, and the reactivity of the nitrenium ion with DNA of cIQ are similar to IQ and that none of these factors account for the differences in mutagenic potency of these analogues in Ames assays. Oligonucleotides were synthesized that contain the C8-dGuo adduct of cIQ in the frameshift-prone CG-dinucleotide repeat unit of the NarI recognition sequence. We have examined the in vitro translesion synthesis of this adduct and have found it to be a strong replication block to Escherichia coli DNA polymerase I, Klenow fragment exo(-) (Kf(-)), E. coli DNA polymerase II exo(-) (pol II(-)), and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Previous studies by Fuchs and co-workers identified E. coli pol II as the polymerase responsible for two-base deletions of the C8-dGuo adduct of N-acetyl-2-aminofluorene in the NarI sequence. Our observation that pol II is strongly inhibited by the C8-dGuo adduct of cIQ suggests that one of the other SOS inducible polymerases (E. coli pol IV or pol V) is required for its bypass, and this accounts for the greatly attenuated mutagenicity in the Ames assays as compared with IQ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / chemistry
  • Benzimidazoles / metabolism*
  • Benzimidazoles / pharmacology*
  • Carcinogens / chemistry
  • Carcinogens / metabolism
  • Carcinogens / pharmacology
  • Cattle
  • DNA / metabolism*
  • DNA Replication / drug effects
  • Male
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Mutagens / chemistry
  • Mutagens / metabolism*
  • Mutagens / pharmacology*
  • Nuclear Magnetic Resonance, Biomolecular
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Quinolines / pharmacology
  • Rats
  • Rats, Sprague-Dawley


  • 2-amino-3-methylimidazo(1,2-d)naphthalene
  • Benzimidazoles
  • Carcinogens
  • Mutagens
  • Quinolines
  • DNA
  • calf thymus DNA
  • quinoline