Role of retinoic acid in the modulation of benzo(a)pyrene-DNA adducts in human hepatoma cells: implications for cancer prevention.
Carcinogen-DNA adducts could lead to mutations in critical genes, eventually resulting in cancer. Many studies have shown that retinoic acid (RA) plays an important role in inducing cell apoptosis. Here we have tested the hypothesis that levels of carcinogen-DNA adducts can be diminished by DNA repair and/or by eliminating damaged cells through apoptosis. Our results showed that the levels of total DNA adducts in HepG2 cells treated with benzo(a)pyrene (BP, 2 μM)+RA (1 μM) were significantly reduced compared to those treated with BP only (P=0.038). In order to understand the mechanism of attenuation of DNA adducts, further experiments were performed. Cells were treated with BP (4 μM) for 24h to initiate DNA adduct formation, following which the medium containing BP was removed, and fresh medium containing 1 μM RA was added. The cells were harvested 24h after RA treatment. Interestingly, the levels of total DNA adducts were lower in the BP/RA group (390 ± 34) than those in the BP/DMSO group (544 ± 33), P=0.032. Analysis of cell apoptosis showed an increase in BP+RA group, compared to BP or RA only groups. Our results also indicated that attenuation of BP-DNA adducts by RA was not primarily due to its effects on CYP1A1 expression. In conclusion, our results suggest a mechanistic link between cellular apoptosis and DNA adduct formation, phenomena that play important roles in BP-mediated carcinogenesis. Furthermore, these results help understand the mechanisms of carcinogenesis, especially in relation to the chemopreventive properties of nutritional apoptosis inducers.
Zhou
Guo-Dong
GD
Department of Environmental and Occupational Health, School of Rural Public Health, Texas A&M University System, College Station, Texas 77030-3303, USA. gzhou@ibt.tamhsc.edu
Richardson
Molly
M
Fazili
Inayat S
IS
Wang
Jianbo
J
Donnelly
Kirby C
KC
Wang
Fen
F
Amendt
Brad
B
Moorthy
Bhagavatula
B
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001564:Benzo(a)pyrene / Q000378:metabolism* / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism*; D004260:DNA Repair; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D018736:DNA Adducts; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D014212:Tretinoin; D019363:Cytochrome P-450 CYP1A1