Genetic polymorphism in the 5 '-flanking region of human CYP1A2 gene: Effect on the CYP1A2 inducibility in humans

A genetic polymorphism was identified in the 5'-flanking region of human CY P1A2 gene, and its effect on the transcriptional activation of the CYP1A2 g ene was investigated. Nucleotide sequence analysis revealed the existence o f a point mutation from guanine (wild type) to adenine (mutated type) at po sition -2964 in the gene. This point mutation was detected by a polymerase chain reaction-restriction fragment length polymorphism method using DdeI o r BslI restriction enzyme, and was proven to be genetically inherited. Alle le frequency in 116 Japanese subjects showed 0.77 and 0.23 for the wild and mutated types of allele, respectively. The point mutation caused a signifi cant decrease of CYP1A2 activity measured by the rate of caffeine 3-demethy lation in Japanese smokers (p < 0.05), Gel retardation analysis showed the existence of protein bound to the polymorphic locus. These results suggest that this polymorphism is a causal factor of decreased CYP1A2 inducibility.