사람 CYP1A2*1C와 CYP1A2*1F 유전형질다형성에서의 Intron-1결합단백질에 의한 유발 조절

초록

Single nucleotide polymorphisms (SNPs) of human CYP1A2 gene have been studied well in hepatic drug-metabolizing activities of several ethnic groups. Particularly, gene polymorphisms of G-3858A (G-2964A, CYP1A2*1C) in 5’-flanking region and/or A-164C (A734C, CYP1A2*1F) in intron 1 region of the human CYP1A2 gene were confirmed to be associated with high enzyme activity and inducibility in smokers. The frequencies of the CYP1A2*1C and CYP1A2*1F alleles were 0.219 and 0.646, respectively, similar to the values determined in other ethnic populations . Seven genotypes were identified with respect to the both variant alleles. In total subjects and smokers, the log activity was normally distributed (W=0.9818, p=0.064 and W=0.9634, p=0.093, respectively). As expected, the mean CYP1A2 activity (metabolic ratio=MR) of smokers (MR=19.45±8.57, ranged from 5.0 to 39.58) was significantly higher (p=0.0002) than that of nonsmokers (13.93±6.26, ranged from 2.41 to 29.53). Among the examined nonsmokers, no significant differences in CYP1A2 activity were evaluated between the genotypes. However, the CYP1A2 inducibility in smokers affected by both CYP1A2*1C and CYP1A2*1F alleles, not either. The subjects with G-3858/A-164 haplo-genotype showed a higher inducibility than those with G-3858/C-164 or A-3858/A-164 haplo-genotype. In addition, EMSA test for CYP1A2*1F allele specific site was clearly distinguished by intron 1 binding proteins (In1BPs) between A-164 and C-164 alleles without stimulation of 3-MC or TCDD, showing no effects of In1BPs on the basal CYP1A2 activity. After stimulation with 3-MC or TCDD, however, the binding capacities of In1BPs modulated only in C-164 allele sequence or equally in both sequences of A-164 and C-164 alleles. These results indicate that regulatory factors like In1BPs are specifically distributed in CYP1A2 intron 1 sequences and suggest that regulatory interactions between CYP1A2*1C and CYP1A2*1F alleles can be modulated CYP1A2 inducibility