Activation of PAH and Tumorigenesis

The enzymes primarily responsible for Phase I metabolism of PAHs are (a) the cytochrome P450s (CYPs) CYPlAl, CYP1A2, and CYPIBI, (b) NADPH 

PAH diol epoxide-DNA adducts have not only been detected in rodent tissues in experimental systems after PAH exposure, but have also been identified in (a) populations exposed to complex mixtures containing PAHs, (b) foundry workers (Perera et al. 1988 Hemminki et al. 1988), (c) coke oven workers (Rojas et al. 1995 Pavanello et al. 1999), (d) cigarette smokers (Lodovici et al. 1998 Rojas et al. 1995), (e) chimney sweeps (Pavanello et al. 1999), and (f) populations exposed to smoky coal combustion mixtures (Mumford et al. 1993). Some bay- or fjord-region diol epoxides form DNA adducts in the human p53 tumor suppressor gene at sites that are hotspots for lung cancer (Smith et al. 2000). 

The role of depurinating adducts and apurinic sites in the PAH-induced cancer process is controversial and has yet to be fully elucidated. There are lines of evidence that both support and refute this theory. In support of this theory, the levels of depurinating adducts of B[a]P correlated with mutations in the H-ras oncogene in DNA isolated from mouse skin papillomas initiated by this compound (Chakravarti et al. 1995). It is well known that the initiation of skin tumors in mice is associated with the formation of mutations in the H-ras gene [reviewed by Ross and Nesnow (1999)]. DB[a,/]P treatment of mouse skin forms papillomas which contain the H-ras codon 61 (CAA to CTA) mutation. These same mutations were induced in early preneoplastic skin within one day after DB[a,/]P treatment and appear to be related to DB[a,/]P-Ade-depurinating adducts. Studies have shown that apurinic 

It should be noted that to date the o-qninone/ROS mechanism has only been described in vitro. There are no reports that that PAH o-qninones are formed in vivo from B[a]P and are stable enough to redox cycle and indnce ROS. B[a]P-7,8-qninone has been the most intensely studied o-quinone and has been fonnd to addnct to DNA in vitro (Balu et al. 2004, 2006), bnt not in vivo (Nesnow et al. 2005). B[a] P-7,8-qninone induces DNA breaks (Park et al. 2008) and indnces ROS in vitro (Flowers-Geary et al. 1996). Current thonght is that B[a]P-7,8-qninone mediates its in vitro biological effects through ROS formation in vitro. 

While the majority of studies on tumor promotion have focused on mouse skin, there are cancers in other organs that are applicable to this model. Bladder 

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