Interplay between vitamin D and the drug metabolizing enzyme CYP3A4

Abstract

Cytochrome P450 3A4 (CYP3A4) is a multifunctional enzyme involved in both xenobiotic and endobiotic metabolism. This review focuses on two aspects: regulation of CYP3A4 expression by vitamin D and metabolism of vitamin D by CYP3A4. Enterohepatic circulation of vitamin D metabolites and their conjugates will be also discussed. The interplay between vitamin D and CYP3A4 provides new insights into our understanding of how enzyme induction can contribute to vitamin D deficiency. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Figure 1

Proposed mechanism that enterohepatic circulation delivers vitamin D derivatives to the intestine and 1α,25(OH)₂D₃ induces intestinal CYP3A4 expression via VDR-mediated pathway.

Figure 2. Longitudinal distribution of TRPV6 and calbindin D9k mRNA in the human small intestine

Tissue samples from four different donors were presented. Isolation of total RNA and real-time quantitative PCR were performed as previously described [53]. A) the levels of TRPV6 mRNA were normalized to the corresponding GAPDH mRNA; B) the levels of Calbindin D9K mRNA were normalized to villin mRNA.

Figure 3. Tissue-specific metabolism of vitamin D metabolites

Under the constitutive condition in the kidney, CYP27B1 catalyzes 1α hydroxylation of 25OHD₃ for vitamin D activation. While CYP24A1 catalyzes 24R- and 23S-hydroxylation of 25OHD₃ and 1α,25(OH)₂D₃ for vitamin D deactivation. In the liver, CYP3A4 is the most abundant enzyme that catalyzes 4β-hydroxylation of 25OHD₃, and 23R- and 24S-hydroxylation of 1α,25(OH)₂D₃ for vitamin D deactivation.