Nucleic Acids in Chemistry and Biology

and identified and are formally derived from a hypothetical nitrenium ion.^34 This, as an ambident cation,
bonds either from nitrogen to guanine C-8 or from carbon to guanine N-2. Similar adducts have been iden-
tified for many other amines. Thus, azo dyes are first cleaved in vivo by an azoreductase to aromatic
amines and then activated as described above.
Metabolic oxidation is being harnessed to develop new anti-cancer agents, such as the 2-(4-amino-3-
methylphenyl)-benzothiazole, Phortress.^35 Selective uptake and biotransformation of the parent amine
DF-203 by cytochrome CYP1A1 has been shown to be characteristic of human breast tumour cells.
Hydroxylative metabolic deactivationof this toluidine can be blocked by fluorination, as in 5F-203
(Figure 8.14b). Phortress is a lysylamide prodrug of 5F-203, in clinical trial, that is metabolically activated
to give DNA adducts in vivoand cause cell arrestin sensitive cells, while cells lacking the ArH signalling
pathway show a much-reduced response.
One example of more than usual significance is the mutagenicityof two types of heterocyclic aminethat
are found in cooked meats, where they are formed by the pyrolysis of tryptophan and glutamine. Sugimura
has identified guanine adducts which are generated by metabolic activation through cytochrome P-450 oxi-
dation and binding to nucleic acids (Figure 8.15).^36 Thus, grilled beef has been estimated to contain nearly
1ppm of Trp-P-1, while up to 80ng of this carcinogen has been isolated from the smoke of a single cigarette!
Aromatic nitro compoundsare found in diesel engine emission, urban air particles and photocopier
black toners and some have been identified as mutagens in the Ames’ test. They can be reduced to aryl
hydroxylamines by anaerobic bacteria in the gut, by xanthine oxidase, or by cytochrome P-450 reductase
to give substrates for the processes described above. The best-studied example is 4-nitroquinoline
N-oxide, which is first reduced to a hydroxylamine and then binds to DNA in vivo, forming characteristic
guanine adducts (Figure 8.16).^37

8.6.2 N-Nitroso Compounds

Nitrosoureas, nitrosoguanidines and nitrosourethanes hydrolyse to give methyldiazonium hydroxide,
MeNNOH, which is a ‘hard’ methylating agent. (In the case of methyl N-nitrosoguanidine
(MNNG), thiol groups may catalyse the in vivomethylation of DNAby this carcinogen). The same methyl-
ating species is produced as a result of the cytochrome P-450 oxidation of a wide range of N-methyl-
nitrosamines, of which dimethylnitrosaminewas the first to be identified as a carcinogen in 1956. The
common metabolic pattern is hydroxylation of one alkyl residue to form a carbinolamine. This breaks
down to give methyldiazohydroxide (Figure 8.17). Many N-nitroso compounds of this type have proved to

306 Chapter 8

HN

N

N

N

N

dR

NH 2

H

N

H

Me

NH 2

R

tryptophan

heat

N

N

N

glutamine

heat

R

NH 2

i

i O

Ar

Figure 8.15 Metabolic activation of heterocyclic amines from amino acids in cooked food and their binding to DNA;
RH or Me. Processes: (i) cytochrome P-450; (ii) DNA binding; and (iii) hydrolysis

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