Genetic Polymorphism in the 5'-Flanking Region of HumanCYP1A2 Gene: Effect on the CYP1A2 Inducibility in Humans

Abstract

A genetic polymorphism was identified in the 5'-flanking region of human CYP1A2 gene, and its effect on the transcriptional activation of the CYP1A2 gene was investigated. Nucleotide sequence analysis revealed the existence of a point mutation from guanine (wild type) to adenine (mutated type) at position -2964 in the gene. This point mutation was detected by a polymerase chain reaction-restriction fragment length polymorphism method using DdeI or BslI restriction enzyme, and was proven to be genetically inherited. Allele 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 significant decrease of CYP1A2 activity measured by the rate of caffeine 3-demethylation 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.

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism

“…This is similar to the Egyptian population 29 but significantly different from that reported in Japanese population. 17 Consequently, absence of association of this SNP with TD in our study seems in order. Since no other reports on association of this SNP with TD are available, comparisons are not possible.…”

“…Primers used for amplification of CYP1A2*1C were F5 0 -GCT ACA CAT GAT CGA GCT ATA C-3 0 and R5 0 -CAG GTC TCT TCA CTG TAA AGT TA-3 0 . 17 Briefly, the PCR was performed in a total reaction volume of 20 ml containing 100 ng of DNA template, 200 mM dNTPs, 0.5 mM of each primer, 0.5 U of Taq polymerase (Roche) and 1 Â PCR reaction buffer. Cycling conditions were initial denaturation at 951C for 5 min followed by 35 cycles of 951C for 45 s, 561C for 45 s, 721C for 1 min and final extension at 721C for 7 min.…”

“…However, only two of these SNPs namely CYP1A2*1C (G4A) and CYP1A2*1F (C4A) have been shown to be of functional significance. 17,18 The CYP1A2*1C (G4A) polymorphism in the upstream region of the human CYP1A2 gene (À3858) results in a significantly reduced induction of this gene among smokers (measured by the rate of caffeine 3-demethylation 17 ). CYP1A2*1F (C4A), an intronic polymorphism was observed in one out of eight healthy volunteers.…”

Genetic susceptibility to Tardive Dyskinesia in chronic schizophrenia subjects: V. Association of CYP1A2 1545 C>T polymorphism

“…We previously investigated two SNPs, CY-P1A2*1C (À3858G4A) in the 3-methylcholanthrene element and CYP1A2*1F (A4C) located in the first intron. Both these variants lead to lesser inducibility among smokers (A allele of CYP1A2*1C; C allele of CYP1A2*1F 12,13 ). We did not observe any association of these two markers with TD.…”

“…11 Additionally, CYP1A2 is induced by polycyclic aromatic hydrocarbons present in cigarette smoke and the reported alleles (marked in bold here) CYP1A2*1C (À3858G4A) and CYP1A2*1F (À163 A4C) lead to low induction in subjects who are smokers, thus influencing the bioavailability of antipsychotic drugs. [11][12][13] Previously, we had investigated the contribution of these two polymorphisms in the susceptibility to TD and did not observe any significant association with TD but observed an increased severity of TD in subjects carrying the A allele of the CYP1A2*1C polymorphism. 14 We had also investigated four other reported amino-acid substitutions in the coding region, but these were found to be monomorphic in our population.…”