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'-deoxythymidine (AZT) caused increased mutant frequencies (Mfs) at the X-linked hypoxanthine-guanine phosphoribosyltransferase (HPRT) and the autosomal thymidine kinase (TK) genes in human lymphoblastoid cells and that there was a significant positive correlation between AZT incorporation into cellular DNA and AZT-induced TK Mfs. In the current study, the mutagenicity of AZT was further evaluated at the autosomal adenine phosphoribosyltransferase (APRT) gene. AZH1 cells, a human lymphoblastoid cell line heterozygous at the APRT locus, were exposed to 300 microM AZT for 0, 1, 3 or 6 days or to 0, 33, 100, 300 or 900 microM AZT for 3 days (n = 5 flasks/group). A cell cloning assay was used to quantitate APRT Mfs. AZT-induced APRT Mf increased with extended duration and with incremental concentrations of AZT exposure. There was a positive correlation (P = 0.022, coefficient = 0.93) between AZT incorporation into DNA and AZT-induced APRT Mfs. RFLP analyses indicated that AZT exclusively induced loss of heterozygosity in APRT mutants. These results, which are consistent with findings on the mutagenicity of AZT at the HPRT and TK genes, indicate the need for further investigations on the potential long-term side effects of AZT on humans, especially those who receive AZT for a prophylactic reason.
Meng
Q
Q
Wadsworth Center, New York State Department of Health, Albany, NY 12201-0509, USA.
Grosovsky
A J
AJ
Shi
X
X
Walker
V E
VE
D000228:Adenine Phosphoribosyltransferase / Q000235:genetics*; D000963:Antimetabolites / Q000633:toxicity; D001402:B-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019656:Loss of Heterozygosity; D016296:Mutagenesis; D009152:Mutagenicity Tests; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D015215:Zidovudine / Q000633:toxicity*
D000963:Antimetabolites; D015215:Zidovudine; D004247:DNA; D000228:Adenine Phosphoribosyltransferase