Studies of mutagenicity and clastogenicity of 5-azacytidine in human lymphoblasts and Salmonella typhimurium

Abstract

5-Azacytidine (5-AzaC) induced mutation in the TK +/− human lymphoblastoid line, TK6, at both the thymidine kinase ( tk) locus as measured by resistance to trifluorothymidine (F 3TdR), and the hypoxanthine-guanine phosphoribosyltransferase ( hgprt) locus, as measured by resistance to 6-thioguanine (6TG). F 3TdR R and 6TG R mutant fractions induced by 5-AzaC were observed after a normal phenotypic expression time and remained stable. Interestingly, 5-AzaC was 5–10 times more mutagenic at the tk locus than the hgprt locus. However, F 3TdR R colonies from 5-AzaC-treated cultures behaved like TK-deficient mutants induced by other chemical mutagens. The TK or HGPRT phenotype had no effect on the toxicity of 5-AzaC, thus eliminating differential toxicity as a potential cause for the observed higher mutability at the tk locus. 5-AzaC did not induce F 3TdR R cells in the parental TK +/+ lymphoblastoid line, indicating that 5-AzaC-induced F 3TdR R variants were not due to a dominant alteration in gene expression. 5-AzaC did not induce chromosomal aberrations in TK6 cells, eliminating clastogenic events as a potential cause for the higher mutability at the tk locus. 5-AzaC was also found to be mutagenic in a forward mutation assay to 8-azaguanine resistance in Salmonella typhimurium.