A role of aryl hydrocarbon hydroxylase inducibility in susceptibility to lung carcinogenesis

Lung cancer mortality has been increasing rapidly in recent years in Japan and is expected to exceed that of stomach cancer in male Japanese in the near future. Although chronic inhalation of cigarette smoke is a major risk factor for the development of lung cancer, it seems important to examine genetic susceptibility to the disease as well. Aryl hydrocarbon hydroxylase (AHH), a drug-metabolism enzyme, is useful in determining the individual differences in genetic susceptibility to lung carcinogenesis. AHH is a microsomal membrane-bound monooxygenase system located in most tissues of the body. In mice, AHH inducibility is under the control of the Ah locus and certain inbred strains of mice are susceptible to AHH induction by 3- methylcholanthrene treatment (Ah responsive strains), while other strains are not (Ah non-responsive strains). A strong correlation was observed between AHH inducibility and tumor incidence in mice. Since AHH is also responsible for the activation to carcinogens of benzo (a) pyrene and other aromatic hydrocarbons in cigarette smoke, it may also be important in humans in the causation of lung cancer. Kellermann et al. investigated the genetics of AHH in a human population and reported that the inducibility of this enzyme was controlled by a single gene locus with 2 dominant alleles. They classified humans as having low, intermediate, or high inducibility of AHH. In addition, they reported a significant positive correlation between the extent of inducibility and susceptibility to lung cancer. Their claim, however, has been both supported and refuted by subsequent investigators. Recently, a close association between development of lung cancer and three polymorphisms of CYP1A1 caused by the presence or absence of one MspI site in the 3'- flanking region, namely, a predominant homozygote pattern (A), a heterozygote pattern (B) and a homozygous rare allele pattern (C), has been reported. The relationship between AHH inducibility and polymorphisms of CYP1A1 had not been investigated previously. Our study indicated that the genotype of C, very frequent in Kreyberg type I, was closely related to high AHH inducibility. Thus, the relationship between AHH inducibility and lung cancer, suggested by Kellermann et al., is supported by our study. Further studies will be needed to confirm the present results. Identification of smokers who have genetically high susceptibility to lung cancer (pattern C), may become important for the prevention of lung cancer.