The Relationship Between DNA-Adduct Formation and Induction of Mutations in the Hypoxanthine-Guanine Phosphoribosyl Transferase (HGPRT) Locus in Human Uroepithelial Cells

Abstract

Abstract To gain an insight on the mechanisms of mutagenesis and carcinogenesis of the human bladder carcinogen 4-aminobiphenyl (ABP) in the target uroepithelia, we analyzed the cellular DNA-adducts and mutational spectra in the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) gene following exposure to N-hydroxy metabolites of ABP. [32P]-postlabelling analyses of DNA isolated from SV-40 immortalized human uroepithelial cells (HUC) exposed to N-hydroxy-4-aminobiphenyl derivatives revealed N-(deoxyguanosin-8-yl)-4-aminobiphenyl (dG-ABP) as the major adduct and N-(deoxyadenosin-8-yl)-4-aminobiphenyl (dA-ABP) as a minor adduct. The adduct profiles of the HUC-DNA obtained at different periods after carcinogen exposure showed that dG-ABP was repaired rapidly while dA-ABP persisted in HUC cultures. DNA sequence analyses of thioguanine resistant mutants of HGPRT showed base deletions (G, bp. 599; A, bp. 608; and A,T bp. 672–673). These results imply that dG-ABP and dA-ABP are repaired at different rates a...