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Figure 1. Basal CYP3A4 and CYP3A5 mRNA expression in HepG2 cells. CYP3A4 and CYP3A5 mRNA levels are shown as relative expression compared with GAPDH mRNA (2-DΔCt ). CYP3A4 is 18.5-times more expressed than CYP3A5 (p < 0.001) compared by t-test. * p < 0.001.
(Figure omitted. See article PDF.)
Figure 2. Effect of atorvastatin treatment on normalized CYP3A4 and CYP3A5 mRNA expression. CYP3A4 and CYP3A5 mRNA levels are shown as relative expression to GAPDH mRNA (2-DΔDΔCt ). (A) After 12-h treatment. (B) After 24-h treatment. Groups were compared by one-way analysis of variance, followed by Dunnett''s Multiple Comparison Test. Data are presented as mean (bars) and standard deviaiton (lines). * p < 0.05
(Figure omitted. See article PDF.)
Figure 3. Hypothetical CYP3A4 and CYP3A5 transcription activation process, modulated by activated PXR--RXR or CAR--RXR heterodimers. Statins are ligands for PXR and CAR, and this might contribute to the increase in CYP3A mRNA expression. CYP3A4 has two binding sites for heterodimers (PXRE and XREM), while CYP3A5 has only one binding site (PXRE). This difference might explain the minor atorvastatin induction observed for CYP3A5 when compared with CYP3A4. CAR: Constitutive androsterone receptor; PXR: Pregnane X receptor; PXRE: PXR responsive elements; RXR: Retinoid X receptors; XREM: Xenobiotic-responsive enhancer module.
(Figure omitted. See article PDF.)
CYP3A4 & CYP3A5: function & variants
Cytochrome P450 (CYP) 3A4 and 3A5 belong to a subfamily of enzymes that are highly expressed in the liver, gastrointestinal tract and kidney that metabolize a large number of chemically unrelated xenobiotics through hydroxylation, oxidation and reduction reactions [1]. A recent study demonstrated that CYP3A4 and CYP3A5 metabolize 37% of the 200 most consumed drugs on the US market [2].
Besides the mediation of Phase 1 drug biotransformation, CYP3A4 and CYP3A5 are involved in the metabolism of cholesterol, steroid hormones and other lipids that are important in intracellular signaling pathways [3]. A reviewed list of CYP biotransformation reactions and substrates was compiled by Brown et al. [1].
Variants in the CYP3A4 and CYP3A5 genes have been associated with differences in gene expression in the liver [4--6] and a differential response to several drugs, such as tacrolimus, verapamil and saquinavir [7--10]. The most relevant variants of these genes are CYP3A4*1B (rs2740574) and CYP3A5*3C (rs776746). An updated list...