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Review
. 2017;18(12):1095-1105.
doi: 10.2174/1389200218666170531112038.

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

Ogheneochukome Lolodi  1 , Yue-Ming Wang  1 , William C Wright  1   2 , Taosheng Chen  1   2
Affiliations
Review

Differential Regulation of CYP3A4 and CYP3A5 and its Implication in Drug Discovery

Ogheneochukome Lolodi et al. Curr Drug Metab. 2017.

Abstract

Background: Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body's natural defense against xenobiotics by increasing the rate of xenobiotic efflux and metabolic inactivation. Xenobiotic metabolism typically involves conversion of parent molecules to more soluble and easily excreted derivatives in reactions catalyzed by Phase I and Phase II drug metabolizing enzymes.

Methods: We performed a structured search of peer-reviewed literature on P450 (CYP) 3A, with a focus on CYP3A4 and CYP3A5.

Results: Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor (PXR), CYP3A4 and CYP3A5 enzymes. The CYP3A enzymes are a subset of the numerous enzymes that are transcriptionally activated following the interaction of PXR and many ligands.

Conclusion: Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them.

Keywords: CYP3A4; CYP3A5; Cancer; cytochrome P450; drug discovery; drug resistance; drug-drug interactions.

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Conflict of interest statement

CONFLICT OF INTEREST

The authors declare no financial or any other conflicts of interest. This work was supported by ALSAC, St. Jude Children’s Research Hospital, National Institutes of Health National Institute of General Medical Sciences [Grants RO1-GM086415, RO1-GM110034, & R35-GM118041], and National Cancer Institute [Grant P30-CA21765].

Figures

Figure 1
Figure 1
CYP3A cluster on Chromosome 7. The gene cluster on 7q21-22 contains four functional genes and two pseudogenes (CYP3AP1 and CYP3AP2). CYP3A43 is the only gene in the cluster that is in an opposite direction.
Figure 2
Figure 2
Sequence homology between CYP3A4 (blue) and CYP3A5 (red). The amino acid sequences of both proteins are 84.1% identical. Alignment was done by EMBOSS Pairwise alignment: vertical strokes indicate identical amino acids, colons indicate amino acids with related side chains, and full stops represent amino acids without similarities in their side chains.
Figure 3
Figure 3
Crystal structures of CYP3A4 and virtual structure of CYP3A5. PyMol was used to depict the crystal structures of free (A) and erythromycin-bound (B) CYP3A4, which were culled from Protein Data Bank with entry numbers 1TQN and 2J0D respectively. The hypothetical structure of ritonavir-bound CYP3A5 (C) was obtained using the molecular simulation methods of Saba et al. [144]. Heme is in blue, and ligand in red
See this image and copyright information in PMC

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