The genotoxic air pollutant 3-nitrobenzanthrone and its reactive metabolite N-hydroxy-3-aminobenzanthrone lack initiating and complete carcinogenic activity in NMRI mouse skin.
3-Nitrobenzanthrone (3-NBA), a genotoxic mutagen found in diesel exhaust and ambient air pollution and its active metabolite N-hydroxy-3-aminobenzanthrone (N-OH-3-ABA) were tested for initiating and complete carcinogenic activity in the NMRI mouse skin carcinogenesis model. Both compounds were found to be inactive as either tumour initiators or complete carcinogens in mouse skin over a dose range of 25-400nmol. Topical application of 3-NBA and N-OH-3-ABA produced DNA adduct patterns in epidermis, detected by (32)P-postlabelling, similar to those found previously in other organs of rats and mice. 24h after a single treatment of 100nmol DNA adduct levels produced by 3-NBA (18+/-4 adducts/10(8) nucleotides) were 6 times lower than those by 7,12-dimethylbenz[a]anthracene (DMBA; 114+/-37 adducts/10(8) nucleotides). In contrast, identical treatment with N-OH-3-ABA resulted in adduct levels in the same range as with DMBA (136+/-25 adducts/10(8) nucleotides), indicating that initial DNA adduct levels do not parallel tumour initiating activity. When compounds were tested for tumour initiating activity by a single treatment followed by twice-weekly applications of TPA, DNA adducts formed by DMBA, but not by 3-NBA or N-OH-3-ABA, were still detectable 40weeks after treatment. When tested for activity as complete carcinogens by twice-weekly topical application, 3-NBA and N-OH-3-ABA produced identical DNA adduct profiles in mouse skin, with adducts still detectable after 40weeks. Only 3-NBA produced detectable adducts in other organs.
Research Group Genetic Alterations in Carcinogenesis, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Heinz H
HH
Schmeiser
Gerhard
G
Fürstenberger
Takeji
T
Takamura-Enya
David H
DH
Phillips
Volker M
VM
Arlt
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000393:Air Pollutants / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004817:Epidermis / Q000378:metabolism / Q000473:pathology; D005260:Female; D051379:Mice; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D001335:Vehicle Emissions
D000393:Air Pollutants; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D018736:DNA Adducts; C543590:N-hydroxy-3-aminobenzanthrone; D001335:Vehicle Emissions; D015127:9,10-Dimethyl-1,2-benzanthracene; C117220:3-nitrobenzanthrone