PAH o-Quinones

Since the AKR pathway produces electrophilic and redox-active PAH o-quinones, two major types of DNA lesions are possible. These are the covalent adducts in which the PAH o-quinones are bound to bases in DNA and the oxidative lesions that can arise due to the production of ROS (Scheme 6.6). 

Two types of covalent PAH o-quinone-DNA adducts are possible. The first type involves the formation of stable covalent adducts that may result from either 1,4- or 1,6-Michael addition of the N2-exocyclic amino group of dGuo or the N exocyclic amino group of dAde. Evidence exists for these adducts in reactions of B [a] P-7,8-dione with either deoxyribonucleosides or bulk DNA [94, 95]. In the former case,... 

Scheme 6.7 Unusual stable PAH o-quinone dCuo adducts.

The second type of PAH o-quinone covalent adduct involves formation of depurinating adducts that result from 1,4- or 1,6-Michael addition of the N7 ring nitrogen of guanine or adenine. Evidence for these adducts were observed in vitro by reaction of PAH o-quinones with deoxyribonudeosides under acidic conditions or by reaction of PAH o-quinones with calf thymus DNA [97]. These adducts were fully characterized by NMR and LC/MS. Recently, interest in the covalent PAH o-quinone adducts has diminished based on the accumulated evidence that PAH... 

Yu, D., Berlin, J.A., Penning, T.M., and Field, J.M. (2002) Reactive oxygen species generated by PAH o-quinones cause change-in-function mutations in p53. Chem. Res. Toxicol., 15, 832-842. 

Park, J.-H., Gelhaus, S., Vedantam, S., Olivia, A., Batra, A., Blair, I.A., Field, J., and Penning, T.M. (2008) The pattern of p53 mutations caused by PAH o-quinones is driven by 8-oxo-dGuo formation while the spectrum of mutations is determined by biological selection for dominance. Chem. Res. Toxicol, 21, 1039-1049. 

Park, J.-H., Gopishetty, S., Szewczuk, L.M., Troxel, A.B., Harvey, R.G., and Penning, T.M. (2005) Formation of 8-oxo-7,8-dihydro-2 -deoxyguanosine (8-oxo-dGuo) by PAH o-quinones involvement of reactive oxygen species and copper(II)/copper(I) redox cycling. Chem. Res. Toxicol, 18,1026-1037. 

PAHs are metabolized by a variety of xenobiotic-metabolizing enzymes (Baird et al., 2005). CYP and epoxide hydrolase eonvert the PAH into PAH-diols and these products are transformed in metabolites, potentially, carcinogenic, by the CYP aetion, forming PAH diol-epoxides or by the Aldo-keto-reductase action, generating PAH o-quinones. PAHs can be also activated by CYP and by peroxidases, forming the reactive cations radicals, which bind, covalently, to DNA. Intermediary products formed are still metabolized by enzymes of phase 11, resulting in metabolites more polars and soluble in water becoming ready to be excreted by the body (Shimada, 2006). 

Tsuruda L, Hou Y, Penning TM Stable expression of rat dihydrodiol dehydrogenase (AKR1C9) in human breast MCF-7 cells results in the formation of PAH-o-quinones and enzyme mediated cell death. Chem Res Toxicol 2001, 14 856-862. 

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