How Bulky of Base Adducts can be Responsible for Clastogenicity rather than Mutagenicity?

Authors: Kikuchi Y , Galbreath HE , Kobayashi R , Kudou S , Matsumoto K , Hasegawa A , Saito T , Sato K , Honma T , Yamamoto A , Arai H , Kadoma Y , Kawaguchi S , Furuya K , Kobune M , Nakamura T and Yu F Sasaki

DOI: 10.23880/act-16000256

Volume 8, Issue 1

Abstract

Two types of TK mutants are induced by genotoxic factors; normally growing (NG) TK mutants due to point mutations of targeted TK locus, and slowly growing (SG) mutants due to gross structural changes involving the growth-regulating gene outside targeted TK locus. In this study, human lymphoblstoid WTK1 cells were used to consider how bulky n- alkylated bases can induce SG mutants. For this purpose, n-alkyl methanesulfonates (AMS) having an n-alkyl group with 3-7 carbons [n-propy methanesulfonate (PMS), n-butyl methanesulfonate (BMS), n-pentyl methanesulfonate (PeMS), n- hexyl methanesulfonate (HexMS), and heptyl methanesulfonate(HepMS)] were synthesized. n-alkyl methanesulfonates having n-alkyl groups with 1-7 carbons induced NG mutants, but n-alkyl methanesulfonates having n-alkyl groups with ≥4 carbons but not with ≤3 carbons induced SG mutants. n-Alkyl methanesulfonates having n-Alkyl groups with ≥4 carbons have been shown to induce bulky adducts that cause disturbances to the helical DNA structure and are removed by nucleotide excision repair. It could be considered that n-alkyl groups with ≥4 carbons causing disturbances to the helical DNA structure induce SG mutants to result in clastogenicity rather than mutagenicity.

Keywords: Bulky adducts; n-Alkyl methanesulfonates; Slowly growing TK mutant; Normally growing TK mutants; Clastogenicity; Mutagenicity

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