PAH derivatives

Areas in which additional information is still needed relates to the role and relative importance of different adducts and the mechanisms by which they initiate cells. General principles are developing which will allow better predictions to be made at each of the stages of chemical carcinogenesis outlined in Table I. The ultimate goal therefore, would be, by a combined analysis of all these steps, to predict accurately the carcinogenicity of newly discovered or untested PAH derivatives. 

Model computational studies aimed at understanding structure-reactivity relationships and substituent effects on carbocation stability for aza-PAHs derivatives were performed by density functional theory (DFT). Comparisons were made with the biological activity data when available. Protonation of the epoxides and diol epoxides, and subsequent epoxide ring opening reactions were analyzed for several families of compounds. Bay-region carbocations were formed via the O-protonated epoxides in barrierless processes. Relative carbocation stabilities were determined in the gas phase and in water as solvent (by the PCM method). 

Fig. 22 Aza-PAH derivatives, their carbocyclic parent compounds, and model bay-region carbocations formed via DEs.

Atkinson, R., J. Arey, W. P. Harger, D. Hemig, and P. A. McElroy, Hydroxynitro-PAH and Other PAH Derivatives in California s Atmosphere and Their Contribution to Ambient Mutagenicity, Final Report to the California Air Resources Board, Contract No. A732-154, 1991. 

Several PAHs and hydroxylated or methylated PAH derivatives induce oestrogenic or dioxin-like (antioestrogenic) effects in fish and mammalian cell lines (Santodonato, 1997 Villeneuve et al., 2002 Michallet-Ferrier et al., 2004). For instance, benz[u]anthracene and dibenz[u/2]anthracene elicit oestrogenic responses in vitro (Villeneuve et al., 2002). These two PAHs and five others may also elicit dioxin-like responses, as shown by their induction of ethoxyresorufm-D-deethylase (EROD) activity, a biomarker for cytochrome P450 lAl (Gravato Santos, 2002 Villeneuve et al., 2002). 

Quantum-mechanical calculations have been successfully applied to the study of the carcinogenic pathways of PAH and aza-PAH derivatives, and very good correlations have been shown with the available experimental reactivities of these compounds (23-28). Furthermore, modeling studies of biological electrophiles from PAHs by density functional theory (DFT) methods have given proper descriptions of the charge delocalization modes and NMR characteristics of their resulting carbocations (29-33). 

PAHs to distinguish them from the petrogenic PAHs derived directly from uncombusted petroleum, coal, and their by-products. Natural sources such as forest fires could be important in less inhabited and remote watersheds, but anthropogenic combustion of fossil fuel (e.g., petroleum, coal) and wood is the dominant source of pyrogenic PAHs (Neff, 1979 Bjorseth and Ramdahl, 1983 Ballentine et al., 1996 O Malley et ai, 1997). 

Possible atmospheric reaction products are oxy-, hydroxy-, nitro- and hydroxynitro-PAH derivatives (Baek et al. 1991). Photochemical oxidation of a number of PAHs has been reported with the formation of nitrated PAHs, quinones, phenols, and dihydrodiols (Holloway et al. 1987 Kamens et al. 1986). Some of these breakdown products are mutagenic (Gibson et al. 1978). Reaction with ozone or peroxyacetyinitrate yields diones nitrogen oxide reactions yield nitro and dinitro PAHs. Sulfonic acids have also been formed from reaction with sulfur dioxide. 

Workplace air concentration data are discussed in Section 6.5. Data on ambient atmospheric concentrations of PAHs derived from other sources can be found in the ATSDR Toxicological Profile for Polycyclic Aromatic Hydrocarbons (Agency for Toxic Substances and Disease Registry 1995). 

Knowing which pathways of PAH activation prevail provides a rationale for the detection and quantitation of PAH-derived DNA adducts in population-based studies. Measurement of these adducts provides a method for biomonitoring PAH exposure and provides a risk assessment for susceptibility to diseases such as lung cancer. This could be particularly useful if it is assumed that there is a correlation between DNA adducts, mutational load, and, ultimately, tumor formation. 

Detection and quantitation of PAH-derived DNA adducts requires authentic synthetic standards to act as internal standards and therefore a knowledge of adduct structure. Adduct structure can often be used to provide information on the mechanism of PAH activation that must have occurred. Unfortunately, this is quite challenging since PAH-DNA adducts can be difficult to detect and quantitate since they may be present in only 1 108 nucleotides. State-of-the art methods requiring stable isotope dilution liquid chromatography/multiple reaction monitoring/mass spectrometry (LC/MRM/MS) are necessary to provide sufficient sensitivity to detect these adducts reliably. Additionally, PAH-DNA adducts have different rates of repair and yield different rates of mutation. Thus, each adduct must be assessed so that it can be ranked according to its half-life and miscoding potential. 

The focus of this chapter is on the three different routes of PAH activation that have been reported and how each of these pathways gives rise to its own distinct spectrum of PAH-derived DNA adducts. The detection of these adducts in target tissues, their repair mechanisms, and whether these adducts can produce the expected G — T or A — T transversions is considered. Finally, the reliability of existing analytical methods to detect these adducts with precision and accuracy is discussed. 

In mouse skin studies, a correlation between radical cation depurinating adducts and mutations in the H-ms gene was noted after treatment with B[o]P, DMBA, and DB[a,I]P. The mutations observed were G —> T transversions at codon 13 or A —> T transversions at codon 61, which could thus be explained by the formation of radical cation depurinating DNA adducts that were detected [36]. In a small cohort of seven women who were exposed to either household coal-smoke or smoked cigarettes, three women had modest amounts of the B[o]P-6-N7-Gua adduct that exceeded the B[a]P-6-N7-Ade adduct by 200- to 300-fold [37]. The levels of other PAH-derived DNA lesions were not reported. 

The differences between the behavior of T7 RNA polymerase and RNA Pol II at PAH-derived DNA adducts can be explained by the structural features of the two different enzymes and tbeir active sites as briefly described above. T7 RNA polymerase has a more open, flexible active site when compared to the more tunnel-like, constricted active site of RNA Pol II. Computer modeling using the crystal structures of T7 RNA polymerase and yeast RNA Pol II suggest that the open active site of the phage polymerase permits larger bulky adducts to enter the site, whereas PAH-derived lesions fit less readily into the eukaryotic... 

Schuetzle D, Lee FSC, Prater TJ (1981) The identification of polynuclear aromatic hydrocarbon (PAH) derivatives in mutagenic fractions of diesel particulate extracts. Intern JEnviron Anal Chem 9, 93-144. 

OPAHs, NPAHs, and alkylated PAH derivatives, as well as other unidentified structural isomers of PAHs. 

Cob is the nonbonding MO (NBMO) coefficient on the carbon atom where the oxirane ring is opened. It is calculated according to the Longuet-Higgins zero sum rule for odd alternant aromatic hydrocarbons [36,65], Incidentally, the first authors to try such NBMO coefficients of exocyclic atoms of odd-alternant PAH derivatives were Dipple, Lawley and Brookes [66] in 1968. 

The last class of lipids being considered here are the hydrocarbons. Hydrocarbon markers include alkanes derived from algae or plant leaves, and polycyclic aromatic hydrocarbons (PAH) derived mainly from crude petroleum and fuel spills. PAH can also be found in combustion products of fuels such as heating oil, gasoline and wood. Coastal sediments act as the ultimate reservoirs for these compounds when they are transported unaltered through the water column. 

A simulation experiment of acute exposure to PAH was performed in fish. A single PAH compound was injected intraperitoneally in fish in different doses depending on the ring number of the compound and the fish weight. The PAH derivatives potentially present in fish after 5 days of metabolism are PAH hydroxy, dihydroxy, glucuronic, and sulphate. 

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