Title: Functional significance of different human CYP1A1 genotypes.
Authors: Crofts, F; Taioli, E; Trachman, J; Cosma, G N; Currie, D; Toniolo, P; Garte, S J
Published In Carcinogenesis, (1994 Dec)
Abstract: At least two different polymorphisms in the human CYP1A1 gene have been associated with an increased risk for tobacco-related lung cancer; however, the functional significance of these polymorphisms has not been determined. We measured CYP1A1 genotypes, gene expression levels and enzymatic activity levels in mitogen-stimulated lymphocytes to determine whether genetic polymorphisms in CYP1A1 alter transcriptional and/or post-transcriptional regulation of the gene. Genotypes were determined at two sites previously associated with lung cancer: a point mutation in exon 7 near the catalytic region of the enzyme and an Msp1 RFLP in the 3' non-coding region of the gene. Variant genotypes at the Msp1 site had no effect on CYP1A1 gene induction, however, variant genotypes at the exon 7 site were significantly associated with increased CYP1A1 gene inducibility. We also observed a significant interaction between the exon 7 polymorphism and smoking on mRNA levels. There was a 3-fold elevation in CYP1A1 enzymatic activity in exon 7 variant genotypes. When Msp1 and exon 7 genotypes were combined, there was an increased CYP1A1 inducibility and enzymatic activity in subjects with the exon 7 polymorphism, and in subjects with both polymorphisms.
PubMed ID: 8001264
MeSH Terms: Adult; Aryl Hydrocarbon Hydroxylases/analysis; Base Sequence; Continental Population Groups/genetics; Cytochrome P-450 Enzyme System; Enzyme Induction; Exons; Female; Genetic Predisposition to Disease; Genotype; Humans; Lung Neoplasms/enzymology; Lung Neoplasms/genetics; Lymphocyte Activation; Male; Middle Aged; Molecular Sequence Data; Polymorphism, Genetic*; Polymorphism, Restriction Fragment Length; Smoking; Transcription, Genetic