Abstract
Variations in the activities of Cytochrome P450s are one of the major factors responsible for inter-individual differences in drug clearance rates, which may cause serious toxicity or inefficacy of therapeutic drugs. Various mRNA level is one of the key factors for different activity of the major P450 genes. Although both genetic and environmental regulators of P450 gene expression have been widely investigated, few studies have evaluated the functional importance of cis- and trans-regulatory factors and environmental factors in the modulation of inter-individual expression variations of the P450 genes. In this study, we measured the mRNA levels of seven major P450 genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5) in 96 liver biopsy samples from Chinese population. Both trans-acting (mRNA levels and non-synonymous SNPs of putative regulator genes) and cis-acting (gene copy number and functional SNPs) factors were investigated to identify the determinants of the expression variations of these seven P450 genes. We found that expression variations of most P450 genes, regulator genes and housekeeping genes were positively correlated at the mRNA level. After partial correlation analysis using ACTB and GAPDH expression to eliminate the effect of global regulators, a UPGMA (Unweighted Pair Group Method with Arithmetic Mean) tree was constructed to reveal the effects of specific regulation networks potentially masked by global regulators. Combined with the functional analysis of regulators, our results suggested that expression variation at the mRNA level was mediated by several factors in a gene-specific manner. Cis-acting genetic variants might play key roles in the expression variation of CYP2D6 and CYP3A5, environmental inducers might play key roles in CYP1A1 and CYP1A2 variation and global regulators might play key roles in CYP2C9 variation. In addition, the functions of regulators that play less important roles in controlling expression variation for each P450 gene were determined.
Highlights
The Cytochrome P450 superfamily is a very large and diverse group of hemoproteins that is present in almost all living organisms
Strong correlations between expression level and enzyme activity have been observed for CYP1A1, CYP1A2, CYP3A4, CYP2C8, CYP2C9, CYP2D6 and CYP2B6, suggesting that the mRNA level may be a major determinant of the total activity of these P450 genes [6,7]
Expression variations of P450s and regulator genes CYP1A1 showed the largest inter-individual difference in expression (138-fold, Table S4), which is consistent with the observation that expression of CYP1A1 was highly inducible by environmental inducers
Summary
The Cytochrome P450 superfamily is a very large and diverse group of hemoproteins that is present in almost all living organisms. About putative functional Cytochrome P450 genes and more than pseudogenes have been identified in the human genome [1,2]. These P450 genes encode enzymes, such as monooxygenase, that play a crucial role in detoxification of exogenous xenobiotics, decomposition of drugs and metabolism of many endogenous compounds, such as hormones, fatty acids, prostaglandin, cholesterol and vitamin D [3,4]. Cytochrome P450 enzymes, which play key roles in Phase I oxidative metabolism, have been extensively investigated due to their great variations in activity in the human population. Strong correlations between expression level and enzyme activity have been observed for CYP1A1, CYP1A2, CYP3A4, CYP2C8, CYP2C9, CYP2D6 and CYP2B6, suggesting that the mRNA level may be a major determinant of the total activity of these P450 genes [6,7]
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