Molecular Mechanisms of Polymorphic CYP3A7 Expression in Adult Human Liver and Intestine

Abstract

Human CYP3A enzymes play a pivotal role in the metabolism of many drugs, and the variability of their expression among individuals may have a strong impact on the efficacy of drug treatment. However, the individual contributions of the four CYP3A genes to total CYP3A activity remain unclear. To elucidate the role of CYP3A7, we have studied its expression in human liver and intestine. In both organs, expression of CYP3A7 mRNA was polymorphic. The recently identified CYP3A7*1C allele was a consistent marker of increased CYP3A7 expression both in liver and intestine, whereas the CYP3A7*1B allele was associated with increased CYP3A7 expression only in liver. Because of the replacement of part of the CYP3A7 promoter by the corresponding region of CYP3A4, the CYP3A7*1C allele contains the proximal ER6 motif of CYP3A4. The pregnane X and constitutively activated receptors were shown to bind with higher affinity to CYP3A4-ER6 than to CYP3A7-ER6 motifs and transactivated only promoter constructs containing CYP3A4-ER6. Furthermore, we identified mutations in CYP3A7*1C in addition to the ER6 motif that were necessary only for activation by the constitutively activated receptor. We conclude that the presence of the ER6 motif of CYP3A4 mediates the high expression of CYP3A7 in subjects carrying CYP3A7*1C.Cytochrome P450 enzymes play a pivotal role in the oxidative, peroxidative, and reductive metabolism of many endogenous compounds, procarcinogens, and drugs. The CYP3A subfamily composed of CYP3A4, CYP3A5, CYP3A7, and CYP3A43 in humans is of special importance because it accounts for as much as 30% of total liver cytochrome P450 content (1). At least 50% of all medicines are metabolized by enzymes of the CYP3A subfamily (2). The most abundant CYP3A isoform in liver and intestine is CYP3A4. Its interindividual hepatic expression varies 60-fold (3), and the in vivo function as assessed by clearance displays at least a 20-fold difference (4). Induction by xenobiotics (e.g. rifampin) and endogenous compounds (e.g. steroid hormones) further modulates the variability of CYP3A4 expression among individuals. The induction of CYP3A4 and most likely that of other CYP3A genes is mediated by the nuclear receptor NR1I2 (pregnane X receptor (PXR) 1 ) (reviewed in Ref. 5). CYP3A4-inducing compounds bind to PXR and stimulate the transcriptional activity of the receptor. Additional nuclear receptors such as NR1I3 (constitutively activated receptor (CAR)) and NR1I1 (vitamin D receptor) have also been implicated in the transcriptional regulation of CYP3A4 (6, 7). Although the substrate specificity of CYP3A5 is similar to that of CYP3A4, CYP3A5 has been regarded to be less important for drug elimination because it is expressed at much lower levels than CYP3A4 in most livers of Caucasian origin (8). CYP3A43 is expressed at very low levels in adult human livers, accounting for only 0.1-0.2% of CYP3A4 transcripts (9, 10). Therefore, its contribution to the elimination of CYP3A substrates is regarded to be negligible (10). This variability in CYP3A...

CYP3A5*3Polymorphism and Its Clinical Implications and Pharmacokinetic Role

“…Its expression level decreases rapidly after birth and becomes undetectable in most adult livers, except for the subjects carrying one of two promoter variants, CYP3A7*1B and CYP3A7*1C. [6] CYP3A43 is also expressed at very low levels in adult livers, accounting for only 0.1-0.2% of CYP3A transcripts. [7,8] Interestingly, the hepatic expression of CYP3A5 is bimodal, with the high expressor exhibiting 10-30 fold higher CYP3A5 expression levels than the CYP3A5 lower expressor.…”

Sex and CYP3A5 genotype influence total CYP3A activity: high CYP3A activity and a unique distribution of CYP3A5 variant alleles in Ethiopians

“…3 The contribution of CYP3A43 and CYP3A7 to the metabolism of CYP3A substrates in adults is therefore thought to be negligible. 1,3 The total CYP3A catalytic activity is thus mainly because of CYP3A4 and CYP3A5.…”

“…3 The contribution of CYP3A43 and CYP3A7 to the metabolism of CYP3A substrates in adults is therefore thought to be negligible. 1,3 The total CYP3A catalytic activity is thus mainly because of CYP3A4 and CYP3A5. 4 Most substrates for CYP3A4 are also metabolized by CYP3A5, although the relative contribution of CYP3A5 to CYP3A-mediated metabolism may differ for different substrates.…”

Pharmacogenomics Dictate Pharmacokinetics: Polymorphisms in Drug-Metabolizing Enzymes and Drug-Transporters

“…2006;Bluth MH, 2011) [ Table 4]. A number of studies have shown interindividual variability and tissue specificity in the expression of cytochrome P450 gene expression (Koch I, et al, 2002). As a result, patients can be classified into four phenotypes based on the level of a CYP enzyme activity: poor metabolizer (abolished activity), intermediate metabolizer (reduced activity), extensive metabolizer (normal activity), and ultrarapid metabolizer (enhanced activity).…”