© 1994 Oxford University Press
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Functional significance of different human CYPlAl genotypes
Nelson Institute of Environmental Medicine and Kaplan Comprehensive Cancer Center, New York University Medical Center New York, NY, USA
1Present address: Department of Environmental Health Colorado State University
2To whom correspondence should be addressed
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 Mspl RFLP in the 3’ non-coding region of the gene. Variant genotypes at the Mspl site had no effect on CYPlAl gene induction, however, variant genotypes at the exon 7 site were significantly associated with Increased CYPlAl 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 Mspl 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.
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