title: Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days.
abstract: We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N  (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.
authors: Carcinogen-DNA Interactions Section, LCBG, CCR, National Cancer Institute, NIH,  Bethesda, MD 20892-4255, USA.
authors: Kaarthik
authors: K
authors: John
authors: M Margaret
authors: MM
authors: Pratt
authors: Frederick A
authors: FA
authors: Beland
authors: Mona I
authors: MI
authors: Churchwell
authors: Gail
authors: G
authors: McMullen
authors: Ofelia A
authors: OA
authors: Olivero
authors: Igor P
authors: IP
authors: Pogribny
authors: Miriam C
authors: MC
authors: Poirier
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000378:metabolism; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism; D002735:Chlorophyllides / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; 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; D053719:Tandem Mass Spectrometry; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D051760:Xeroderma Pigmentosum Group A Protein / Q000502:physiology*
chemical_list: D016587:Antimutagenic Agents; D002273:Carcinogens; D002735:Chlorophyllides; D018736:DNA Adducts; D016159:Tumor Suppressor Protein p53; D051760:Xeroderma Pigmentosum Group A Protein; C497315:Xpa protein, mouse; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; C007020:chlorophyllin