As noted in Chapter 3, the metabolism of many chemical carcinogens is critical to their carcino- genic action. Thus, one might expect that the susceptibility to the development of neoplastic disease resulting from exposure to a chemical carcinogen will depend on the host’s capability of “activating” the agent to its ultimate form through appropriate metabolic pathways. Genetic al- teration in such pathways can lead to an enhanced or decreased susceptibility of the individual to neoplasia induced by the carcinogenic agent.
Phase I Genes
As discussed in Chapter 3, the principal components of the phase I xenobiotic metabolizing en- zymes are those of the cytochrome P450 family. Table 5.11 lists the cytochrome P450 genes of the human, their chromosomal location where known, the number of amino acids in the gene product, the organs of major expression, and, where known, those carcinogens that are activated by the individual members of the family.
More than two decades ago, a report indicated that high inducibility of the aromatic hydro- carbon hydroxylation pathway was a significant risk factor for human lung cancer (Kellerman et al., 1973). These studies were performed with human lymphocytes, and it was assumed that changes seen in this peripheral tissue reflected changes in the lung, since a high level of inducibility of AHH in lymphocytes was more frequently observed in lung cancer patients than in patients with other diseases. These results became quite controversial, since others were unable to reproduce these data, but more recent studies in Japan have related a specific mutation in a codon of exon 7 in the cytochrome P-450IA1 gene exhibits a different geno- typic distribution between controls and lung cancer patients, as noted in Table 5.12 (Hayashi et al., 1992).
The mutation in the gene is the result of a transition from an adenine residue to that of a guanine, resulting in a change from an isoleucine (Ile) to a valine (Val) residue, as depicted in Figure 5.12. Individuals with the homozygous mutation (Val/Val) tend to develop lung cancer at a greater frequency with lower consumption of cigarettes (Figure 5.13). A different polymor- phism revealed by the restriction enzyme MspI also demonstrated polymorphisms in the Japa- nese population that were related to increased risk of lung cancer, especially at low numbers of cigarettes smoked (Nakachi et al., 1991). Studies in other races, especially in Scandinavians, did
Key: B(a)P, benzo(a)pyrene; 2-AAF, 2-acetylaminofluorene; 4-ABP, 4-aminobiphenyl; Glu-P-1, 2-amino-6-methyldipy- rido[1,2-a:3′,2′-d]imidazole; IQ, 2-amino-3-methylimidazo[4,5-f]quinoline; AFB1, aflatoxin B1; Trp-P-2, 3-amino-1- methyl-5 H-pyrido[4,3-b]indole; 2-AF, 2-aminofluorene; NDEA, N-nitrosodiethylamine; NNK, 4-(methylnitrosamino)-
1-(3-pyridyl)-1-butanone; 6-AC, 6-aminochrysene.
Adapted from Kawajiri and Fujii-Kuriyama, 1991, with permission of authors and publisher.