FUNCTIONAL-SIGNIFICANCE OF DIFFERENT HUMAN CYP1A1 GENOTYPES

At least two different polymorphisms in the human CYP1A1 gene have bee n associated with an increased risk for tobacco-related lung cancer; h owever, the functional significance of these polymorphisms has not bee n determined. We measured CYP1A1 genotypes, gene expression levels and enzymatic activity levels in mitogen-stimulated lymphocytes to determ ine whether genetic polymorphisms in CYP1A1 alter transcriptional and/ or post-transcriptional regulation of the gene. Genotypes were determi ned at two sites previously associated with lung cancer: a point mutat ion 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 Msp 1 site had no effect on CYP1A1 gene induction, however, variant genoty pes at the exon 7 site were significantly associated with increased CY P1A1 gene inducibility. We also observed a significant interaction bet ween the exon 7 polymorphism and smoking on mRNA levels. There was a 3 -fold elevation in CYP1A1 enzymatic activity in exon 7 variant genotyp es. When Msp1 and exon 7 genotypes were combined, there was an increas ed CYP1A1 inducibility and enzymatic activity in subjects with the exo n 7 polymorphism, and in subjects with both polymorphisms.