The effect of pentachlorophenol on DNA adduct formation in p53 wild-type and knockout mice exposed to benzo[a]pyrene

Previous studies have shown that pentachlorophenol (PCP) has both potentiative and antagonistic effects on the genotoxicity of benzo[a]pyrene (B[a]P). It has been suggested that these effects are due to inhibition and/or induction of enzymes involved in the biotransformation of B[a]P [Carcinogenesis 16 (1995) 2643]. However, B[a]P [J. Biol. Chem. 274 (1999) 35240] and a metabolite of PCP, tetrachlorohydroquinone (TCHQ) [Chem. Biol. Interact. 105 (1997) 1], induce p53 protein synthesis in vitro. To investigate this effect further, C57BL/6Tac trp53+/+ (wild-type, WT) and C57BL/6Tac trp53−/− (knockout, KO) mice were exposed to 55 μg B[a]P/g BW alone or in combination with 25 μg/g PCP. Hepatic and lung DNA were analyzed for the major B[a]P DNA adduct, 7R,8S,9S-trihydroxy-10R-(N2-2′-deoxyguanosyl)-7,8,9,10-tetrahydro-B[a]P (BPDE–N2G) and other minor adducts using the 32P-postlabeling assay. BPDE–N2G adducts were detected in all animals exposed to B[a]P. Similar adduct levels were observed in WT mice exposed to 55 μg/g B[a]P compared with KO mice exposed to B[a]P alone or in combination with PCP. Interestingly, hepatic and lung BPDE–N2G adducts were decreased in WT mice exposed to B[a]P with PCP (P<0.05). Total DNA adducts in the liver (P<0.05) were also decreased in WT mice exposed to B[a]P and PCP. Total DNA adducts in either hepatic or lung DNA isolated from KO mice were not different in mice treated with PCP and B[a]P. These results suggest that the decrease in BPDE–N2G adducts observed in WT mice may be a result of p53 accumulation or induction of repair pathways in response to damage induced by PCP.