Active carcinogens

The mechanism of carcinogenesis by PAHs is believed to involve alkylation of an informational macromolecule in a critical, but at present unknown, manner. Such an interaction with a protein has been modelled by alkylation of a peptide this showed a conformational change occurred on alkylation. It has not yet been possible to study the structure of DNA alkylated by an activated carcinogen this is because DNA is a fiber and the structural order in it is not sufficient for a crystal structure determination. However the crystal structures of some alkylated portions of nucleic acids are described, particularly some nucleosides alkylated by chloromethyl derivatives of DMBA. In crystals of these alkylation products the PAH portion of the adduct shows a tendency to lie between the bases of other nucleoside... 

So we are still left with two models of the stereochemistry of DNA alkylated by a PAH diol epoxide the PAH either lies in a groove of DNA or else tries to intercalate between the bass of DNA. Since it is covalently bonded to a base it must cause considerable distortion if it tries to lie between the bases. However, the stacking observed in the crystalline state seems to argue for partial intercalation. We will need crystal structures of at least one appropriately alkylated polynucleotide before this problem can be resolved. And when this is done it will be just the beginning of the answer to the problem of alkylation of DNA by activated carcinogens. The subsequent question is, what is the lesion in DNA that is important in carcinogenesis, and then what does it cause to happen so that tumor formation is initiated ... 

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 ease of formation of PAH cation-radicals is related to their IP. Above a certain IP, activation by one-electron oxidation becomes unlikely because the removal of one electron by the active forms of P450 or peroxidases is more difficult. A cutoff IP above which one-electron oxidation in not likely to occur was tentatively proposed to be about 7.35 eV (Cavalieri and Rogan 1995). For example, 7,12-dimethylbenz[a]-anthracene has an IP of 7.22 eV and is extremely carcinogenic. Benz[a]anthracene has an IP of 7.54 eV and is very weak in this sense. The active carcinogenicity of dibenz[a,h]anthracene (IP 7.61 eV) is not attributable to the one-electron mechanism. It is worth noting that the one-electron transfer is only one of the operating mechanisms of carcinogenesis. 

If a carbon atom bearing a positive charge is bound with the methyl group, the reaction path consists of a methyl proton loss. This is the intrinsic property of methyl derivatives in the cation-radical state. The deprotonation generates a benzylic-type radical that is rapidly oxidized to a so-called benzylic carbocation, which reacts with a nucleophile as shown in Scheme 3.70. From Scheme 3.70 it is clear that BP-6-methyl can act as an active carcinogen (Cavalieri and Rogan 1995). 

Cole, R.J., Aghamohammadi, Z., Cole, J. Henderson, L. (1982) Short-term tests for trans-placcntally active carcinogens. Multiple-dose regimes in the transplacental mieronueleus test. Mutat. Res., 105, 115-120... 

In this context, oxygen free radicals have been linked to many diseases other than cancer. There is much evidence that such free radicals may be developed in any kind of inflamed tissues and in chronically irritated organs the free radicals produced may convert exogenous chemicals to active carcinogens. 

Aryl hydrocarbon hydroxylase (AHH) is a complex mixed function oxidase enzyme which converts polycyclic aromatic hydrocarbons such as DMBA to more hydrophilic and readily excretable products. During this process metabolites that are more carcinogenic than the parent compound can be produced. The distribution of MFO enzymes, their activity, and the balance between conversion of procarcinogens to active carcinogens and their detoxification is probably a... 

Huberman, E., and L. Sachs. Mutability of different genetic loci in mammalian cells by metabolically activated carcinogenic polycyclic hydrocarbons. 

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