Fjord region

Johansen, H.R., O.J. Rossland, and G. Becher. 1993. Congener specific determination of PCBs in crabs from a polluted fjord region. Chemosphere 27 1245-1252. 

Fig. 10.12. Upper part The K, M, bay, and fjord regions of three isomeric tetracyclic aromatic hydrocarbons (benz[a]anthracene (BaA, 10.31), chrysene (CR, 10.32), and benzo[c]phenanthrene (BcPh, 10.33)). Lower part. The three pairs of enantiomeric (S,R)- and (R,S)-K-region epoxides and...

In contrast, the pathway best known to yield adduct-forming metabolites (the ultimate carcinogens) is the formation of dihydrodiol epoxides, usually referred to as diol epoxides . This pathway involves three steps a) formation of an M-region epoxide, b) its hydration to the M-region dihydrodiol, and c) epoxidation of the latter at the vicinal C=C bond bordering the bay or fjord region. 

The formation and reactivity of dihydrodiol epoxides is now illustrated for benzo[a]pyrene (BaP, 10.34, Fig. 10.13), one of the most extensively investigated PAHs and a highly active carcinogen. However, far from being exclusive to BaP, this toxification pathway is known to occur for a number of PAHs containing a bay or fjord region. 

The high reactivity of bay-region (and fjord-region) diol epoxides has intrigued chemists for years. Numerous experimental and computational studies have been carried out, affording a wealth of information on the mechanisms by which bay-region diol epoxides form adducts with nucleic acids and are deactivated by reaction with protective nucleophiles or by hydrolysis. Indeed, the hydration of diol epoxides forms unreactive tetrahydroxy metabolites known as tetrols (10.39, Fig. 10.14,a). 

S. Vepachedu, N. Ya, H. Yagi, J. M. Sayer, D. M. Jerina, Marked Differences in Base Selectivity between DNA and the Free Nucleotides upon Adduct Formation from Bay- and Fjord-Region Diol Epoxides , Chem. Res. Toxicol. 2000, 13, 883 -890. 

Figure 14.8 Potent PAH carcinogens with a bay/fjord region.

Substitution at bay/fjord region benzo ring J, if ring substitution at each and every bay/fjord region benzo ring Prevent formation of bay/ fjord region diol epoxide... 

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). 

Melendez-Colon, V. J., Luch, A., Seidel, A., and Baird, W. M. (2000). Eormation of stable DNA adducts and apurinic sites upon metabolic activation of bay and fjord region polycyclic aromatic hydrocarbons in human cell cultures. Chem Res Toxicol 13, 10-17. 

Oehme, M., Mano, S., Brevik, E., and Knutzen, J. 1989. Determination of polychlorinated dibenzofuran (PCDF) and dibenzo-p-dioxin (PCDD) levels and isomer patterns in fish, Crustacea, mussel and sediment samples from a fjord region polluted by Mg-production. Fresenius Z. Anal. Chem., 335, 987-997. 

The diol epoxide pathway does, however, account for the structure-activity relationships in the bay region, methylated bay region, and fjord region PAH, since diol epoxides would not form without this structural feature. 

Human recombinant AKRs have been shown to catalyze identical reactions for bay region trans-dihydrodiols (phenanthrene, chrysene, B[a]P, benz[a]anthracene), methylated bay region trarcs-dihydrodiols (5-methylchrysene and 7,12-DMBA), and fjord region trans-dihydrodiols (B[g]C) [18-20], Thus far, no human AKR has been show to be an efficient catalyst of the oxidation of the potent proximate carcinogen HR,12R-dihydroxy-dihydro-DB[a,l]P. Interestingly, this metabolic pathway of... 

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