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The nucleoside reverse transcriptase inhibitor zidovudine (AZT) induces genotoxic damage that includes centrosomal amplification (CA > 2 centrosomes/cell) and micronucleus (MN) formation. Here we explored these end points in mice deficient in DNA repair and tumor suppressor function to evaluate their effect on AZT‐induced DNA damage. We used mesenchymal‐derived fibroblasts cultured from C57BL/6J mice that were null and wild type (WT) for Xpa, and WT, haploinsufficient and null for p53 (6 different genotypes). Dose‐responses for CA formation, in cells exposed to 0, 10, and 100 μM AZT for 24 hr, were observed in all genotypes except the Xpa^(+/+)p53^(+/−) cells, which had very low levels of CA, and the Xpa^(−/−)p53^(−/−) cells, which had very high levels of CA. For CA there was a significant three‐way interaction between Xpa, p53, and AZT concentration, and Xpa^(−/−) cells had significantly higher …