Allelic expression imbalance of the human CYP3A4 gene and individual phenotypic status

Abstract

The human cytochrome P450 3A4 (CYP3A4) plays a dominant role in the metabolism of numerous clinically useful drugs. Alterations in the activity or expression of this enzyme may account for a major part of the variation in drug responsiveness and toxicity. However, it is generally accepted that most of the known single nucleotide polymorphisms in the coding and 5'-flanking regions are not the main determinants for the large inter-individual variability of CYP3A4 expression and activity. We show that the allelic variation is critically involved in determining the individual total hepatic CYP3A4 mRNA level and metabolic capability. There exists a definite correlation between the total CYP3A4 mRNA level and allelic expression ratio, the relative transcript level ratio derived from the two alleles. Individuals with a low expression ratio, exhibiting a large difference of transcript level between the two alleles, revealed extremely low levels of total hepatic CYP3A4 mRNA, and thus low metabolic capability as assessed by testosterone 6beta-hydroxylation. These results present a new insight into the individualized CYP3A4-dependent pharmacotherapy and the importance of expression imbalance to human phenotypic diversity.

Unique CYP3A4 genetic variant in Brazilian tuberculosis patients with/without HIV

“…These results demonstrate that, in Brazilians, CYP3A4*1B and CYP3A4*1A have a peculiar distribution. Although many studies have connected CYP3A4 genotypes with ethnicity (36,40,41,(46)(47)(48), in this study the genotype distribution revealed no correlation with patient skin color. Besides this, it was observed that the GG genotype was twice as common in non-white people (66.7%).…”

“…Regarding the differential allelic expression of CYP3A4 associated with many xenobiotics (36), and the previous evidence indicating that smoking is causatively associated with active TB (37,38), alterations in the CYP3A4 regulatory region may influence the activity or expression of the enzyme, and could be related to variation in drug interaction, including tobacco compounds. In this study, the tobacco consumption frequency among patients was twice (32%) as high as that previously described in the Brazilian population; approximately 16%, ranging from 9.5% in Salvador to 21.2% in Porto Alegre and Rio Branco cities (39).…”

“…Transcriptional and genotyping analysis using liver samples from 18 Caucasian donors found an association between allelic constitution and CYP3A4 mRNA levels. Due to this, the authors suggested that CYP3A4 alleles or haplotypes lead to the total hepatic CYP3A4 mRNA, producing a different enzymatic level that may have an effect on the metabolic capability, as indirectly measured through testosterone 6β-hydroxylation (36).…”

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

“…35 Inheritance of ASE in the CYP3A4 gene expression has been previously reported. 22 Accordingly the observed ASE in CYP1A2 gene expression may be inherited to cause variation in enzyme activity similar to genetic polymorphisms. Several studies reported lack of genotype-phenotype relationship in CYP1A2.…”

Suppression of Cytochrome P450 3A4 Function by UDP-Glucuronosyltransferase 2B7 through a Protein-Protein Interaction: Cooperative Roles of the Cytosolic Carboxyl-Terminal Domain and the Luminal Anchoring Region

“…In many cases, such a discrepancy can be explained by a single-nucleotide polymorphism. However, the frequencies of CYP3A4 singlenucleotide polymorphisms, which are able to suppress enzyme function, are rare and seem to be unable to explain the aforementioned discrepancy (Hirota et al, 2004;Lakhman et al, 2009). It is also unconvincing that micro-RNAdependent downregulation underlies the polymorphic function of CYP3A4 (Takagi et al, 2008;Pan et al, 2009;Singh et al, 2011).…”