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

Abstract

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 ([3H]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 4NQOO dose (5.10−7 or 1.10−7M) is given within 3 h of the first 4QNO 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 4QNO 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.