Year: 2008
Type: article
Abstract: Variation in activity of cytochrome P450s is one of the major factors responsible for interindividual difference in drug clearance rate which may cause serious toxicity or inefficacy of clinically used drugs.Such variation was reported to be determined at mRNA level for major P450 genes albeit it to a various degree.Little is known about mechanisms underlying the huge expression variation of most P450 genes among individuals.Identification of genetic variants affecting expression levels of P450 genes can lead to a cost-effective personalized medicine.This dissertation aims to 1) determine the genetic diversity and genetic structure of the CYP1A1_1A2 region; 2) search for determinants of interindividual variation in expression level of seven cytochrome P450 genes; 3) identify cis-acting genetic variants affecting the expression level of CYP1A1 and CYP1A2.Single nucleotide polymorphisms in a 39.6kb segment encompassing the whole CYP1A1 and CYP1A2 genes and the spacer region were identified.The linkage disequilibrium structure, haplotypes and tagSNPs in this region were determined.A "humanized" BAC-transgenic mouse line was established as a in vivo platform to study activity of different haplotypes of the human CYP1A1_1A2 region.Four factors were identified as major determinants of interindividual variability in expression level of P450 genes in human liver with various contribution for each P450 gene.These four factors include ( 1) the functional efficacy of global regulators affecting expression level of most active genes; (2) the expression level of specific P450 regulators; (3) exposure to environmental factors responsible for activation or modulation of activity of specific P450 regulators; (4) the presence of cis-acting genetic variants in P450 genes.At least four major cis-acting regulatory SNPs (rSNP) were demonstrated to exist in regulation of CYP1A1 or CYP1A2 expression.One of the four rSNPs was CYP1A1-940C>T (rs4646418), which is located in a G-rich domain about 1kb upstream of the CYP1A1 transcription initiation site, but affects both CYP1A1 3-MC, 3-methylchorantherene ACTB, beta actin AEI, allelic expression imbalance AER, Allelic expression ratio AHH, aryl hydrocarbon hydroxylase AHR, aryl hydrocarbon receptor AHRE, AHR response element ANOVA, analysis of variance ARNT, ary hydrocarbon receptor nuclear translocator BAC, bacterial artificial chromosome BaP, benzo[a]pyrene BNF, β-naphthoflavone C/EBP, CCAAT/enhancer-binding protein CAR, constitutive androstane receptor CYP, cytochrome P450 CYP1A1, cytochrome P450 1A1 CYP1A2, cytochrome P450 1A2
Author: Zhengwen Jian
Institution: University of Cincinnati
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W171700441