Modulation of the inducibility by intron-1 Binding Proteins(In1BPs) in Human CYP1A2*1C and CYP1A2*1F Genetic Polymorphism

초록

Single nucleotide polymorphisms(SNPs) of human CYP1A2 gene have been studied well in 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 con-firmed to be associated with high enzyme activity and inducibility in smokers.(중략) However, there were no known regulatory factors affecting the activity and/or inducibility, particularly in CYP1A*1F intron mutation site. Here, 137 Korean unrelated healthy volunteers aged 21~33years(23.1 ± 1.9,82 nonsmokers and 55 regular smokers) were phenotyped for CYP1A2 by HPLC analysis of urinary caffeine metabolites[(1,7U ± 1,7x)1,3,7x], and genotyped by PCR-RFLP analysis with their genomic DNAs. 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=.0064 and W=0.9634, P=0.093, respectively). As expected, the mean CYP1A2 activity(metabolic ration=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 from2.41 to 29.53). Among the examined nonsmokers, no significant differences in CYP1A2 activity were evaluated between the genotyes. However, the CYP1A2 inducibility in smokers affected by both CYP1A2*1C and CYP1A2*1F alleles, not either. The subjects with G-3858/C-164 haplo-genotype showed a higher inducibility than those with G-3858/C-164 or A-3858/A-164 haplo-genotype. (중략)These results indicate that regulator factors like In1BPs are specifically distributed in CYP1A2 intron 1 sequences and suggest that interactions between CYP1A2*1C and CYP1A2*1F alleles can e modulated CYP1A2 inducibility.