EXPRESSION OF CYP1A1 GENE IN PATIENTS WITH LUNG-CANCER - EVIDENCE FOR CIGARETTE SMOKE-INDUCED GENE-EXPRESSION IN NORMAL LUNG-TISSUE AND FOR ALTERED GENE-REGULATION IN PRIMARY PULMONARY CARCINOMAS

The major polycyclic aromatic hydrocarbon inducible-cy-tochrome P4501A1 gene (CYP1A1) is presumed to be important in pulmonary carcinogenesis and toxicology because its product, the cytochrome P4501Al-dependent (CYPlAl-de-pendent) monooxygenase, transforms selected xenobiotics (including polycyclic aromatic hydrocarbon procarcinogens in cigarette smoke) to potent carcinogenic metabolites. CYPIAI messenger RNA (mRNA) expression has not, however, been previously demonstrated in human pulmonary tissue. This report defines CYP1A1 gene expression in normal lung tissue and primary pulmonary carcinoma tissue obtained at thoracotomy from 56 patients with lung cancer. When Northern blot hybridization analyses were performed, 17 of 19 (89%) and zero of five (0%) samples of normal lung tissue from active cigarette smokers and nonsmokers, respectively, expressed the normal 2.8-kilobase CYPIAI mRNA. In addition, a time-dependent decrease in expression of the CYPIAI gene was noted in normal lung tissue from individuals who were former smokers, with a decrease in expression occurring as early as 2 weeks following cessation of cigarette smoking. Expression became undetectable in all patients who had stopped smoking more than 6 weeks prior to study. When CYPIAI gene expression was evaluated in lung cancers, mRNA levels were detectable in one of four (25%) tumors from nonsmokers; two of 24 (8%) tumors from former smokers; and seven of 15 (47%) tumors from cigarette smokers. In addition, an approximately 10-kilobase CYPIAI RNA species, which was not detectable in normal lung tissue, was observed in five of ten (50%) of the lung cancers that expressed the CYPIAI gene. There was no positive association between CYPIAI expression and lung cancer histologic cell type nor between CYPIAI mRNA levels in matched normal lung tissue and tumor tissue from patients with lung cancer. These results demonstrate a positive association between active cigarette smoking and CYPIAI gene expression in normal human lung tissue. Moreover, CYPIAI gene expression was documented in many pulmonary carcinomas, and altered regulation of the gene was also observed in several lung tumors. [J Natl Cancer Inst 82: 1333-1339, 1990]. © 1990 Oxford University Press.