INFLUENCE OF AROMATIC HYDROCARBON RECEPTOR-MEDIATED EVENTS ON THE GENOTOXICITY OF CIGARETTE-SMOKE CONDENSATE

The role of aromatic hydrocarbon receptor (AhR)-mediated events on the genotoxicity of mainstream cigarette smoke condensate was investigate d. lit vitro studies with mouse hepatoma cells stably transfected with a DRE-dependent luciferase reporter indicate that cigarette smoke con densate is able to transform AhR to an active form which is capable of initiating gene transcription, Micronucleus formation in two hepatoma cell lines was used as an index of genotoxicity, Cigarette smoke cond ensate was observed to induce a higher frequency of micronuclei in Hep a1c1c7 cells relative to TAOc1BP(r)c1 cells, which express similar to 10-fold less AhR, Furthermore, the frequency of micronuclei was potent iated when Hepa1c1c7 cells were pretreated with 2,3,7,8-tetrachlorodib enzo-p-dioxin, a high affinity ligand of AhR, These in vitro studies w ere followed by an in vivo experiment with Ahr(+/+) and Ahr(-/-) mice. Animals were dosed for three consecutive days with cigarette smoke co ndensate (0.5-10 mu g/kg/day, i.p. injection). The frequency of micron uclei in reticulocytes and total erythrocytes was determined in periph eral blood samples collected 24 h after the last administration. While condensate was found to increase the incidence of micronucleated reti culocytes in Ahr(+/+) mice, no increase was observed in the null allel e animals. Furthermore, the frequency of micronucleated erythrocytes, a measure of basal chromosome-damaging activity, was slightly but sign ificantly higher in Ahr(+/+) relative to Ahr(-/-) mice. Together, thes e data suggest that cigarette smoke contains chemicals which transform the AhR to an active transcription factor and AhR-regulated enzyme in duction plays an important role in mediating the genotoxicity of this complex environmental pollutant.