Allele-specific expression and gene methylation in the control of CYP1A2 mRNA level in human livers

Abstract

The basis for interindividual variation in the CYP1A2 gene expression is not fully understood and the known genetic polymorphisms in the gene provide no explanation. We investigated whether the CYP1A2 gene expression is regulated by DNA methylation and displays allele-specific expression (ASE) using 65 human livers. Forty-eight percent of the livers displayed ASE not associated to the CYP1A2 mRNA levels. The extent of DNA methylation of a CpG island including 17 CpG sites, close to the translation start site, inversely correlated with hepatic CYP1A2 mRNA levels (P ¼ 0.018). The methylation of two separate core CpG sites was strongly associated with the CYP1A2 mRNA levels (P ¼ 0.005) and ASE phenotype (P ¼ 0.01), respectively. The CYP1A2 expression in hepatoma B16A2 cells was strongly induced by treatment with 5-aza-2 0 -deoxycytidine. In conclusion, the CYP1A2 gene expression is influenced by the extent of DNA methylation and displays ASE, mechanisms contributing to the large interindividual differences in CYP1A2 gene expression.

Allele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome

“…ASE has been considered as an important indicator for the presence of functional cisregulatory variants (Pastinen and Hudson 2004). ASE and ASM could be tightly coupled by the same cis-regulatory variants (Ghotbi et al 2009;Milani et al 2009). Similar to gene expression, methylation or ASM can be considered as quantitative traits for population genomic analysis.…”

High CYP2A6 Enzyme Activity as Measured by a Caffeine Test and Unique Distribution of CYP2A6 Variant Alleles in Ethiopian Population

“…Expression and activity of drug metabolizing enzymes is governed by complex traits involving allele-specific genetic and epigenetic variations involving multiple genes (Ghotbi et al, 2009), as well as environmental factors such as dietary constituents (Aklillu et al, 2002). Therefore, future studies involving advanced models to characterize effect of interaction between multiple gene polymorphisms and environmental factors on the expression and activity of CYP enzymes are needed.…”

Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

“…Liver microsomes from previously established liver banks (ethical committee approval numbers 440/97, 112/97, 95:169, 98-089, 429-01, S 079-03, 03-602, 541-31/1) were used to estimate propofol 4-hydroxylation [24,25]. Analysis was performed according to Court et al [26] using propofol concentration 5 μM, which is below the Michaelis constant (K m ) value [7].…”