Role of metabolic polymorphisms in lung carcinogenesis]

Metabolism of most chemical carcinogens in humans is thought to occur in two distinct phases. The carcinogens exert their effect only after being metabolically activated to intermediates (phase I), which are capable of binding to DNA and causing mutations. The most ubiquitous phase I catalysts are the cytochrome P450s (CYPs). There is convincing epidemiological evidence that lung cancer risk associated with polycyclic aromatic hydrocarbons (PAHs) is mediated in part by aryl hydrocarbon hydroxylase (AHH), which is used as an indicator of the phenotype of CYP1A1. Since AHH is responsible for the activation PAHs in cigarette smoke, it may be important in the causation of lung cancer. Kellermann et al. reported a significant positive correlation between AHH inducibility and susceptibility to lung cancer. The finding, however, has been both supported and refuted by subsequent investigators. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. A close association between development of lung cancer and homozygous rare genotypes in MspI and Ile-Val polymorphisms of CYP1A1 gene has been recently reported in some Japanese populations. The association between GSTM1 polymorphism and lung cancer risk is not so strong, however. Following the phase I reaction, phase II enzymes such as glutathione S-transferases (GSTs) are responsible for detoxification of activated forms PAH-epoxides. GSTs form a superfamily of genes consisting of four distinct families, named Alpha, Mu, Pi and Theta. The GSTM1, GSTT1 and GSTP1 genes are polymorphic in humans. The phenotypic absence of GSTM1 activity is due to a homozygous inherited deletion of the gene, the null genotype. The homozygous deletion of GSTM1 genes has been shown to occur in approximately 50% of the populations of various ethnic origins. The GSTM1 null genotype confrs a moderately increased risk of smoking-related lung cancer, however. Genetically determined susceptibility to lung cancer may depend on the metabolic balance between phase I and phase II enzymes. Risk of lung cancer, especially squamous cell carcinoma is shown to be remarkably increased in individuals with a combination of a homozygous rare allele of the CYP1A1 gene and the nulled GSTM1 gene, compared with those having other combinations of genotypes. Individuals with susceptible genotypes may become important for the prevention of lung cancer.