Benzo pyrene, metabolism structure

FIGURE 2.6 The procarcinogen benzo[a]pyrene oriented in the CYPlAl active site (stereo view) via n- n stacking between aromatic rings on the substrate and those of the complementary amino acid side chains, such that 7,8-epoxidation can occur. The substrate is shown with pale lines in the upper structures. The position of metabolism is indicated by an arrow in the lower structure (after Lewis 1996). 

The reaction of metabolically generated polycyclic aromatic diol epoxides with DNA Ua vivo is believed to be an important and critical event in chemical carcinogenesis Cl,2). In recent years, much attention has been devoted to studies of diol epoxide-nucleic acid interactions in aqueous model systems. The most widely studied reactive intermediate is benzo(a)pyrene-7,8-diol-9,10-epoxide (BaPDE), which is the ultimate biologically active metabolite of the well known and ubiquitous environmental pollutant benzo(a)pyrene. There are four different stereoisomers of BaPDE (Figure 1) which are characterized by differences in biological activities, and reactivities with DNA (2-4). In this review, emphasis is placed on studies of reaction mechanisms of BPDE and related compounds with DNA, and the structures of the adducts formed. 

Figure 3. Structure of major DNA adduct detected in many in vivo systems as a result of metabolic activation of benzo[a]pyrene or the reaction of anti-B[alPDE with DNA jji vitro dR=deoxyribose moiety.

This procarcinogen undergoes metabolic conversion to benzo[a]pyrene diol epoxides, BPDEs (5,28-31), which have been the focus of structural and conformational studies by theoretical and experimental methods. These chemically reactive BPDEs are involved in covalent binding to DNA (13-22). 

Figure 5 Molecular structures of the (+)-/rans-a/i/i-[BP]-,/V2-dG and (-)-cis-anti-[BPJ-A dG adducts formed from the metabolically activated form of the widespread environmental polutant benzo[a]pyrene (BP) and dG. These two adducts have the same S-configuration about the a/i/HBPJ-ClO-A -dG linkage but different arrangements of the OH groups at the 7, 8, and 9 positions of the a/i//-[BP] residue. Each of these two diastereoisomers also has a corresponding stereoisomer with a 10R configuration at CIO (not shown).

The K-region 4,5-oxide of benzo[a]pyrene 4 is also known to bind to nucleic acid, ° although little is known about the structures of the bound adducts. Interestingly, 9-hydroxybenzo [a] pyrene, a spontaneous isomerization product of the metabolicaUy formed benzo [a] pyrene 9,10-oxide, also binds to DNA on further metabolic action. Although the evidence is largely indirect, the K-region 4,5-oxide of 9-hydroxybenzo [a] pyrene seems to be responsible for this binding. 

Generally, the PAH components of wood creosote, coal tar creosote, coal tar, and coal tar pitch are metabolized by oxidative enzymes in the liver and lungs to generate active metabolites that can bind to macromolecules. The metabolic profiles vary among species and compounds, but the components follow the same major reaction pathways. Hence, the metabolites are structurally very similar. The proposed metabolic scheme for a representative PAH, benzo[a]pyrene, is presented in Figure 3-4. The principal... 

Although the PAHs are similar, they have structural differences that are the basis for differences in metabolism and relative carcinogenicity. The metabolism of the more carcinogenic, alternant (equally distributed electron density) PAHs, such as benzo(a)pyrene, benzo(a)anthracene, and dibenz(a,h)anthracene, seems to differ in some ways from that of nonalternant (imeven electron density distribution) PAHs, such as fluoranthene, benzo(b)fluoranthene, benzo(k)fluoranthene, benzo(j)fluoranthene, and indeno(l,2,3-cd)pyrene [31]. As can be seen, most of the studies on the metabolic pathways of PAHs have been done on rodent, therefore little is known on the metabolism of these compounds in nonrodent species. Due to specie differences there may be some slight differences in the enzymes that activate PAHs and in the formation of DNA adducts. 

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