Mutagenicity and loss of heterozygosity at the APRT locus in human lymphoblastoid cells exposed to 3 '-azido-3 '-deoxythymidine

Previous experiments in our research group showed that 3'-azido-3'-deoxythy midine (AZT) caused increased mutant frequencies (Mfs) at the X-linked hypo xanthine-guanine phosphoribosyltransferase (HPRT) and the autosomal thymidi ne kinase (TK) genes in human lymphoblastoid cells and that there was a sig nificant positive correlation between AZT incorporation into cellular DNA a nd AZT-induced TK Mfs, In the current study, the mutagenicity of AZT was fu rther evaluated at the autosomal adenine phosphoribosyltransferase (APRT) g ene, AZH1 cells, a human lymphoblastoid cell line heterozygous at the APRT locus, were exposed to 300 mu M AZT for 0, 1, 3 or 6 days or to 0, 33, 100, 300 or 900 mu M AZT for 3 days (n = 5 flasks/group). A cell cloning assay was used to quantitate APRT Mfs, AZT-induced APRT Mf increased with extende d duration and with incremental concentrations of AZT exposure. There was a positive correlation (P = 0.022, coefficient = 0.93) between AZT incorpora tion into DNA and AZT-induced APRT Mfs, RFLP analyses indicated that AZT ex clusively induced loss of heterozygosity in APRT mutants, These results, wh ich are consistent with findings on the mutagenicity of AZT at the HPRT and TK genes, indicate the need for further investigations on the potential lo ng-term side effects of AZT on humans, especially those who receive AZT for a prophylactic reason.