Nucleic Acids in Chemistry and Biology

be carcinogenic in animals and lead to methylation, ethylation, or propylation of DNA, as described above
(Section 8.5.3).^21

8.6.3 Polycyclic Aromatic Hydrocarbons

The polycyclic aromatic hydrocarbons(PAHs) provided the first example of an industrial carcinogen,
benzo[a]pyrene(BaP). Its identification marked the initial stage in the molecular analysis of hydrocarbon
carcinogenesis, which had begun with Percival Pott’s study of scrotal cancer in chimney sweeps in 1775.
BaP becomes covalently bound to DNA invivo following a series of three metabolic changes.^38 In the first,
cytochrome CYP1A1(formerly P 1 -450) adds oxygen to BaP to give the two enantiomers of BaP-7,8-epoxide.
Next, these are used as substrates for an epoxide hydrolasethat converts them into the two enantiomeric
trans-dihydrodiols. Finally, both diols are again substrates for cytochrome CYP 1A1 and are converted
into three of the four possible stereoisomers of the dihydrodiol-9,10-epoxide, BPDE (Figure 8.18).^39
The carcinogenicity and DNA-binding capability of such dihydrodiol epoxidesis closely linked to ‘Bay
Region’architecture, so called because of the concave nature of this edge of the PAH, which appears to
be strongly recognised by the metabolizing enzyme. Among the products that have been characterised are
adducts with guanine N-2, guanine N-7, guanine O-6 and adenine N-6. These are formed as a result of a
rapid intercalation of the BPDE into d(AT)n-rich parts of the DNA helix, which manifest as a red shift in
UV absorption of the hydrocarbon and a negative CD spectrum for the complex. A rate-determining pro-
tonation of the C-10 hydroxyl group then leads to the formation of a carbocation that reacts predominantly
(90%) with water to give the harmless 7,8,9,10-tetra-ol but less frequently (10%) binds to a proximate
nucleic acid base, often a dG residue.
The resulting covalent adducts appear to be of two distinct types. The minor ‘site I’ adducts have the
hydrocarbon still intercalated in an intact DNA helix. The major ‘site II’adducts appear to have the hydro-
carbon lying at an angle to the helix axis, either in the minor groove of a DNA helix or forming a wedge-
shaped intercalation complex. Similar results have been found for chrysene, while the Bay Region

Covalent Interactions of Nucleic Acids with Small Molecules and Their Repair 307

N

N

HN

N

H dR

N

O

N

NH 2

O

N

NO 2

O

N

N

O

HOH N

N

NH

N

dR

O

N

HN

O

NH 2

4-nitroquinoline

N-oxide

reductase

4H

i, ii

Figure 8.16 Reductive activation of 4-nitroquinoline N-oxide and products resulting from its binding to DNA in vivo.
Reagents: (i) DNA in vivo; and (ii) hydrolysis

H 3 C

N

H 3 C

NO

H 3 C

N

H 2 C

N

OH

O H 3 CNNOH

HCHO

H 3 CNN

MAOM

Figure 8.17 Cytochrome P-450 oxidation of dimethylnitrosamine and its conversion into methyl azo-oxymethanol
(MAOM) en route to DNA methylation