US EPA

2147682 

Journal Article 

Mechanisms from Frameshift Mutations: Insight from Aromatic Amines 

Hoffmann, GR; Fuchs, RPP 

1997 

Yes 

Chemical Research in Toxicology
ISSN: 0893-228X
EISSN: 1520-5010 

NIOSH/00236537 

10 

4 

347-359 

Mechanisms of frameshift mutation induction as investigated in studies using aromatic amines were reviewed. The review focused on the results of studies investigating the mutagenicity of N-2-(acetylamino)fluorene (53963) (AAF), N-2-aminofluorene (153786) (AF), and related compounds. The general characteristics of frameshift mutations and mutagens were described. Frameshift mutations generally involve the gain or loss of one or two base pairs, which results in altering the reading frame of the genetic code. Frameshift mutagens may stimulate mutation formation by reacting covalently with DNA or by interacting with DNA in a noncovalent manner. Intercalation between DNA base pairs by acridines represent an example of a noncovalent interaction. Models of frameshift mutation induction were discussed. The Streisinger slippage model is the most well known model. It postulates that frameshift mutations are generated by slippage, or localized pairing out of register, occurring during the replication of DNA. Slippage will leave an unpaired base or a few bases bulged out of the helix. Nick processing is a model that was proposed to explain acridine induced mutagenicity in bacteriophage T4. Nick processing, according to the model, depends on the DNA nicking activity of T4 topoisomerase and the polymerase and exonuclease activities of T4 DNA polymerase. The general effects of aromatic amines on the DNA structure were discussed. AAF, AF, and other aromatic amines require metabolic activation to electrophilic species in order to express mutagenicity and carcinogenicity. AAF, AF, and the related derivative N-2-(acetylamino)-7-iodofluorene (AAIF) form adducts at the C-8 position of guanine in the DNA structure. This results in localized distortions of the helical DNA structure, AAF showing the most pronounced effect and AF and AAIF smaller effects. Studies examining the mutagenicity of AAF, AF, and AAIF were described. The mechanisms of AAF and AF mutagenicity were discussed. AAF mutagenicity in bacterial systems is characterized by the induction of -1 frameshift mutations in monotonous runs of a single base and -2 frameshift mutations in regions containing alternating guanine/cytidine base pairs. AF causes fewer distortions in the DNA structure and is less efficient in inducing frameshift mutations than AAF. In the case of AAF, slippage mechanisms can explain the induction of both -1 and -2 frameshift mutations.