**DNA Damage Caused by Polycyclic Aromatic Hydrocarbons: Mechanisms and Markers**

Balam Muñoz and Arnulfo Albores

*Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del I.P.N. México* 

### **1. Introduction**

124 Selected Topics in DNA Repair

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Polycyclic Aromatic Hydrocarbons (PAHs) are a group of chemicals that occur naturally in coal, crude oil and gasoline. Incomplete combustion of organic material results in emission of PAHs (ATSDR, 1996). These molecules consist of two or more aromatic rings fused in linear, angular or cluster arrangements (Fig. 1) and by definition are composed of hydrogen and carbon. PAHs containing up to six fused aromatic rings are often known as "small" PAHs while those containing more than six aromatic rings are called "large" PAHs. As pure chemicals, these compounds are colorless, white or pale yellow solids. Their physicochemical properties, vapor pressure and solubility vary according to their molecular weight. PAHs possess a highly characteristic UV absorbance spectra although some may be fluorescent (Fetzer & Biggs, 1994). PAHs are ubiquitous and persistent as a consequence of natural (forest fires and volcanic eruptions) and human activities (Jongeneelen, 2001). PAHs may distribute in water, soil and the atmosphere according to different weather and geographical factors. Although industrial activity such as coke manufacturing or asphalt production are major contributors to PAH emissions, incineration, power generation and several mobile sources also emit a considerable amount of PAHs. Significant sources of PAHs in surface waters include deposition of airborne PAHs, municipal wastewater discharge, urban storm-water runoff, and industrial waste. Food groups that tend to have the highest levels of PAHs include charcoal broiled or smoked meats, leafy vegetables, grains, and vegetable fats and oils (Yu, 2005). Therefore, workers of these industries and the general population are continually exposed to different concentrations of PAH mixtures. The Agency for Toxic Substances and Disease Registry (ATSDR) has grouped 17 PAHs according to their health effects (ATSDR, 1996). The United States Environmental Protection Agency (EPA) has designated 28 PAH compounds as priority pollutants (EPA, 2009) (Table 1). The International Agency for Research on Cancer (IARC) has classified some these compounds as carcinogenic (group 1) or likely carcinogenic (group 2A) to humans, for example benzo[*a*]pyrene and dibenz[*a,h*]anthracene, respectively (IARC, 2010). Finally, the National Institute of Standards and Technology has created a classification of PAHs according to their symbols, molecular formulas, class and notation among other properties (NIST, 2010).

The most common mechanism of carcinogenesis induced by PAHs is DNA damage through the formation of adducts. Alternatively, in the presence of reactive oxidative species, DNA

DNA Damage Caused by Polycyclic Aromatic Hydrocarbons: Mechanisms and Markers 127

Acenaphthene 83-32-9 Dibenz(a,j)acridine, 224-42-0 Acenaphtylene 208-96-8 Dibenzo(a,h)anthracene 53-70-3 Benzo(a)anthracene 56-55-3 Dibenzo(a,e)fluoranthene 5385-75-1 Benzo(a)phenanthrene (chrysene) 218-01-9 Dibenzo(a,e)pyrene 192-65-4 Benzo(a)pyrene 50-32-8 Dibenzo(a,h)pyrene 189-64-0 Benzo(b)fluoranthene 205-99-2 Dibenzo(a,l)pyrene 191-30-0 Benzo(j)fluoranthene 205-82-3 7H-Dibenzo(c,g)carbazole 194-59-2 Benzo(k)fluoranthene 207-08-9 7,12-Dimethylbenz(a)anthracene 57-97-6 Benzo(g,h,i)perylene 191-24-2 Fluorene 86-73-7 Benzo(j,k)fluorene (fluoranthene) 206-44-0 Indeno(1,2,3-cd)pyrene 193-39-5 Benzo(r,s,t)pentaphene 189-55-9 3-Methylcholanthrene 56-49-5 Dibenz(a,h)acridine 226-36-8 5-Methylchrysene 3697-24-3 Phenanthrene 85-01-8 Pyrene 129-00-0 1-Nitropyrene 5222-43-0 Anthracene 120-12-7

After exposure, these molecules induce expression of phase I and II metabolizing enzymes (Shimada, 2006) including aldo-ketone reductases, cytochrome P-450s, catechol-Omethyltransferase, epoxide hydrolase, peroxidases, glutathione S-transferases, Nacetyltransferases, sulfotransferases, and other enzymes catalyzing conjugation reactions

There are three main pathways for activation of PAHs: the formation of a PAH radical cation in a metabolic oxidation process involving cytochrome P450 peroxidase, the formation of PAH-o-quinones by dihydrodiol dehydrogenase-catalyzed oxidation and finally the creation of dihydrodiol epoxides, catalyzed by cytochrome P450 enzymes (Guengerich, 2000). The most common mechanism of metabolic activation of PAHs, such as benzo[a]pyrene (B[a]P), is via the formation of bay-region dihydrodiol epoxides e.g. benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), via CYP450 and epoxide hydrolase (EH) (Fig. 2). The most important enzymes in the metabolism of PAHs are CYPs 1A1, 1A2, 1B1 and 3A4. CYP1A1 is highly inducible by PAHs such as B[a]P and some polyhalogenated hydrocarbons. Recombinant human CYP1A1 metabolizes compounds such as B[a]P, 2 acetylaminofluorene and 7,8-diol,7-12-dimethylbenz[a]anthracene (Kim, et al., 1998). CYP1A2 and CYP1B2 are also inducible by the exposure to PAHs. In fact, these enzymes share the same mechanism with which PAH molecules interact with, the aryl hydrocarbon receptor (AhR). The AhR is present in the cytoplasm as a complex with other proteins such as heat shock protein 90 (Hsp90), p23 and AhR-interacting protein. After forming a complex with PAHs, the Hsp90 is released and the AhR-PAH complex translocates to the nucleus (Fig 3). Here, it creates a heterodimer with a ARNT (Ah Receptor Nuclear Translocator) and

Table 1. US EPA priority polycyclic aromatic hydrocarbons.

(Williams & Phillips, 2000).

**2.1 Phase I metabolism of PAHs** 

1 CAS (Chemical Abstracts Service) registry number

Name CAS 1 Name CAS

damage can also result. In this chapter, we review the mechanisms of damage caused by exposure to PAHs, factors involved in repairing the damage, and the important role of biomarkers.
