Aryl Hydrocarbon Receptor Facilitates DNA Strand Breaks and 8-Oxo-2′-deoxyguanosine Formation by the Aldo-Keto Reductase Product Benzo[a]pyrene-7,8-dione

Abstract

Polycyclic aromatic hydrocarbon (PAH)oPolycyclic aromatic hydrocarbons (PAHs) 2 are ubiquitous environmental pollutants that include over 200 compounds with two or more fused benzene rings. PAHs are formed as a result of incomplete combustion of fossil fuels (e.g. coal and oil) and are present in car and diesel exhaust and smoked or charbroiled food (1-3). They are also found in cigarette smoke condensate and tobacco products and are suspect agents in the causation of human lung cancer (4, 5). PAHs must be metabolically activated to reactive genotoxins to cause their mutagenic and carcinogenic effects.Two major metabolic activation pathways are possible starting from the proximate PAH carcinogen (Ϫ)B[a]P-7,8-transdihydrodiol (Fig. 1). The P4501A1/1B1 pathway converts (Ϫ)B[a]P-7,8-trans-dihydrodiol to yield (ϩ)-anti-7,8-dihydroxy-9␣,10␤-epoxy-7,8,9,10-tetrahydroB[a]P (6 -8). This diol epoxide forms stable N 2 -2Ј-deoxyguanosine (dGuo) adducts in vitro and in vivo (9, 10) and leads to mutation in H-ras (11) and may account for mutations in "hot spots" in p53 observed in lung cancer (12). The G to T transversions most often observed in these genes might arise because of the action of one or more trans-lesional by-pass DNA polymerases that read through stable diol-epoxide DNA adducts with low processivity and fidelity (13,14).As an alternative, human aldo-keto reductases (AKR1A1 and AKR1C1-AKR1C4) catalyze the NADP ϩ -dependent oxidation of (Ϯ)B[a]P-7,8-trans-dihydrodiol to produce the electrophilic and redox-active B[a] P-7,8-dione (15, 16). In this pathway, AKRs convert B[a]P-7,8-trans-dihydrodiol to form a ketol that rearranges to a catechol. The catechol then undergoes two subsequent one-electron oxidations to yield the fully oxidized o-quinone. Once formed, B[a]P-7,8-dione amplifies reactive oxygen species (ROS) by entering futile redox cycles that deplete cellular reducing equivalents (e.g. NADPH) (17). PAH * This work was supported, in whole or in part, by National Institutes of Health Grants RO1-CA39504 and P30-ES013508 (to T. M. P.) and RO1-CA130038 (to I. A. B.

Reprint of “In utero exposure to benzo[a]pyrene increases adiposity and causes hepatic steatosis in female mice, and glutathione deficiency is protective”

“…Some BaP metabolites are arylhydrocarbon receptor ligands (Park et al, 2009). Arylhydrocarbon receptor constitutively represses fatty acid synthesis genes in mouse liver and in human hepatoma cells and hepatocytes (Tanos et al, 2012).…”

“…BPDE forms bulky DNA adducts in the nucleus and mitochondria and is mutagenic (Allen and Coombs, 1980;Denissenko et al, 1996;Mass et al, 1993). BaP-7,8-dione is an arylhydrocarbon receptor (AHR) ligand, enabling it to be shuttled to the nucleus, where it undergoes redox cycling, generating reactive oxygen species (ROS) and oxidative DNA lesions, such as 8-oxo-7,8-dihydro-2 -deoxyguanosine (8-OHdG) (Park et al, 2009). Glutathione transferase-mediated conjugation with glutathione (GSH) is a major Phase II biotransformation/detoxification pathway for BPDE and BaP-7,8-dione metabolites of BaP (Jernström et al, 1996;Romert et al, 1989;Xue and Warshawsky, 2005).…”

Benzopyrene Inhibits Differentiation of Human SH-SY5Y Neuroblastomain Culture in Cells

“…It has been suggested that the AhR antagonist activity is due to the formation of a-NF-cytosolic AhR complexes that fail to undergo transformation [23]. It was also reported that a-NF attenuated BaP-7,8-dione-mediated DNA strand breaks [24]. As shown in Figure 4 The expression of TGase protein shows the degree of differentiation of SH-SY5Y neuroblastoma cells.…”

Impact of the Airborne Particulate Matter onthe Human Health

“…Besides ROS formation, the metabolic activation of PAHs by P450 cytochromes (CYP1A1/1B1) forms reactive molecules, epoxides, that may form bulky adducts to the DNA. The formation of such adducts is a well-known process in cells exposed to PAHs, such as benzo[a]pyrene (BaP) (Park et al, 2009). BaP is one of the organic molecules present in fine PM, and this organic fraction released from particles could activate such processes.…”