Enhanced bioreduction of 4-nitroquinoline 1-oxide by cultured ataxia telangiectasia cells.

When dermal fibroblast strains derived from ataxia telangiectasia (AT) and clinically normal donors were exposed to 4-nitroquinoline 1-oxide (4NQO) and their DNA subjected to velocity sedimentation analysis in alkaline sucrose gradients, the incidence of single-strand interruptions detected in the AT strains (AT2BE, AT3BI and AT4BI) was 1.4-1.8 times higher than that seen in the seven normal controls. Cellular uptake of exogenous radiolabelled 4NQO occurred at similar rates in AT and control cultures, arguing against increased influx of the chemical as the root cause of the elevated yield of strand breakage in the former cultures. However, sonicates of each AT strain contained an enhanced capacity to catalyze the reduction of 4NQO to the proximate carcinogen 4-hydroxyaminoquinoline 1-oxide; the differences in bioreductase activity between AT and normal cell sonicates correlated closely with those for the incidence of DNA strand openings in 4NQO-treated cultures. Our data further indicated that these single-strand scissions, seen under alkaline conditions, are not manifestations of intermediate reactions in the multistep excision repair process operative on 4NQO lesions because: (i) the interruptions were observed at comparable levels in AT2BE and AT3BI cells, the former purportedly deficient and the latter proficient in 4NQO adduct removal; and (ii) cells known to be defective in repairing all types of 4NQO lesions, namely, xeroderma pigmentosum complementation group A fibroblasts, accumulated breaks at normal rates during 4NQO treatment. Consequently, these breaks appear to represent a class of 4NQO lesions which are themselves alkali-labile and therefore become converted to single-strand interruptions in vitro during exposure of DNA to alkali before velocity sedimentation. We conclude that AT strains tend to sustain abnormally high amounts of DNA damage upon 4NQO exposure due to an elevated capacity to bioactivate the inert parent compound into a proximate carcinogen.