Functional significance of a C -> A polymorphism in intron I of the cytochrome P450 CYP1A2 gene tested with caffeine

Aims The cytochrome P450 enzyme CYP1A2 metabolises several drugs and carcin ogens. We wanted to determine how much of the variability of CYP1A2 activit y is explained by a newly discovered gene polymorphism in intron 1. Methods A single nucleotide polymorphism in intron 1 of the CYP1A2 gene at position 734 downstream of the first transcribed nucleotide was identified by DNA sequence analysis. The functional significance of this C/A polymorph ism was assessed in 185 healthy Caucasian non-smokers and in 51 smokers by genotyping and phenotyping using caffeine (100 mg oral dose). Results Out of the total sample, 46% were homozygous for the variant A, 44% were heterozygous, and 10% were homozygous for the variant C. The ratio of 1,7-dimethylxanthine (17X) plus 1,7-dimethyluric acid divided by caffeine in 0-5 h urine samples from 185 non-smokers did not differ significantly be tween the three CYP1A2 genotypes. In the 51 smokers, analysis of variance r evealed significant differences in the 5 h plasma 17X/caffeine ratios betwe en the genotypes (P=0.008, F-test). The mean ratio was 1.37 in carriers of the A/A genotype, 0.88 in heterozygotes and 0.82 in carriers of C/C. The me an difference between the A/A and C/A groups was 0.48 (95% confidence inter val 0.15-0.81; P=0.01). Conclusions The A/A genotype, which may represent a CYP1A2 high inducibilit y genotype, may either be a direct cause of increased CYP1A2 activity, or b e genetically linked to polymorphisms conferring high inducibility. Further studies are needed to define the role of this polymorphism on the pharmaco kinetics of drugs metabolised by CYP1A2 and in the activation of carcinogen s.