The diagnosis of pulmonary carcinoma was made at a lower mean age (4.9 years younger) in the individuals with high aryl hydrocarbon hydroxylase activity than in those with low activity.
The data support the hypothesis that high AHH values may be characteristic of lung cancer patients but show that enzyme values determined from a single tissue, either PAMs or lymphocytes, may not be appropriate for showing whether high AHH inducibility is correlated with lung cancer.
It appears that interesting functionally linked interindividual differences in the CYP1A1 gene have been found and could be of importance in understanding differences in susceptibility to lung cancer.
A recently described restriction fragment length polymorphism for the CYP1A1, which codes for the cytochrome P450 enzyme primarily responsible for the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons, has been found to be associated with lung cancer risk in a Japanese population.
These results suggest that high pulmonary CYP1A1 expression (controlling in part carcinogen DNA-adduct formation) in tobacco smokers, appears to be associated with LC risk.
Human CYP1A1 (cytochrome P(1)450) gene: lack of association between the Msp I restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population.
Three examples of pharmacogenetic risk factors are discussed: the first two are p450 enzymes whose activity has been associated with susceptibility to lung cancer (debrisoquine hydroxylase, aryl hydrocarbon hydroxylase), and the last, N-acetyltransferase, a non-p450 enzyme, has been associated with bladder cancer susceptibility.
Epidemiologic evidence for the association of aryl hydrocarbon hydroxylase and lung cancer is presently problematic because of difficulties in the assay and subsequent confounding factors.
This report defines CYP1A1 gene expression in normal lung tissue and primary pulmonary carcinoma tissue obtained at thoracotomy from 56 patients with lung cancer.
These observations represent the first known demonstration of constitutive (non-induced) CYP1A1 gene expression in human cells and suggest altered regulation of the CYP1A1 gene in selected lung cancer cell lines.
Results reveal: a) an average interindividual variation in AHH activity of approximately 0.25 (coefficient of variation); range of activities among humans and baboon subjects of approximately 40-fold; c) both genetic and environmental determinants of interindividual variation, and d) high AHH activity in humans associated with primary lung cancer.
Recent clinical studies suggest a relationship between high AHH activity and lung cancer associated with cigarette smoking (Kouri, R.E., McKinney, C.E., Slomiany, D.J., Snodgrass, D.R., Wray, N.P., and McLemore, T.L.Cancer Res.42: 5030-5037, 1982).
The apparent lack of association of CypIA1 MspI polymorphism with lung cancer in this area reported in our previous study and the results of the present study indicate that the "true" responsible site for lung cancer susceptibility should be the Ile-Val polymorphism in the catalytic site of CypIA1.
We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence.
Furthermore, together with the lack of association of Msp I polymorphism in the non-coding region of CYP1A1, the locus truly responsible for lung cancer risk among pleural polymorphisms of CYP1A1 appeared to be exon 7 Ile-Val polymorphism.
We have found polymorphisms in the CYP2E1 and CYP1A1 genes associated with lung cancer susceptibility, though there were some discrepancies from observations made by other investigators.
Thus pulmonary CYP1A1 expression (inducibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk.
The risk of developing lung cancer is dramatically (up to 40-fold) elevated in subpopulations having simultaneously high-risk genotypes in CYP1A1 and GSTM1.