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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.

Functional Evaluation of Genetic and Environmental Regulators of P450 mRNA Levels