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 microg B[a]P/g BW alone or in combination with 25 microg/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 microg/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.
Ress
Nancy B
NB
Department of Veterinary Anatomy and Public Health, Texas A&M University, College Station, TX, USA. ress@niehs.nih.gov
Donnelly
Kirby C
KC
George
Susan E
SE
D000818:Animals; D001564:Benzo(a)pyrene / Q000378:metabolism / Q000633:toxicity*; D004247:DNA / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010416:Pentachlorophenol / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; C056612:benzo(a)pyrene-DNA adduct; D001564:Benzo(a)pyrene; D004247:DNA; D010416:Pentachlorophenol