Reduced DNA repair capacity and increased cytotoxicity following split doses of the mutagen 4-nitroquinoline-1-oxide in cultured human cells.

Cultured human fibroblasts were exposed to single doses of 4-nitroquinoline-1-oxide(4NQO) and to two equimolar doses of 4NQO at intervals varying from 0.5 to 12 h. DNA repair synthesis as measured by an unscheduled uptake of tritium-labelled thymidine ([3-H]TdR), cell survival as estimated by the clone-forming capacity, and frequency of chromosome aberrations were used as endpoints. Cells respond with a reduced level of DNA repair synthesis when the second 4NQO dose (5 X 10 minus 7 or 1 X10-minus 7 M) is given within 3 h of the first 4NQO dose. If the interval between the two doses is 5 h or more, the level of DNA repair synthesis which is induced by the second 4NQO dose is comparable to that following a single 60-min 4NQO application. In this 3-h period the cultured cells show an increased sensitivity to the lethal effect and chromosome-damaging action of the second 4NQO dose. The reduced period of DNA repair capacity seems to increase the mutagenic effect of the chemical carcinogen.