Inhibition of CYP2S1 mediated metabolism of anticancer prodrug AQ4N by liarozole

Naveen Singh ,Shawn R White ,Sudhakar Kalagara ,Samuel Kadavakollu

doi:10.7324/japs.2017.70201

Abstract

Pharmacognostical standardization and toxicity profile of the methanolic leaf extract of Plectranthus amboinicus (Lour) SprengPreeja G. Pillai, P. Suresh, Gayatri Aggarwal, Gaurav Doshi, Vidhi Bhatia

Highlights

Cytochrome P450 (CYPs) constitute a large superfamily of enzymes that are haem-thiolate proteins with ubiquitous expression and distribution in diverse life forms including bacteria, fungi, plants and animals (Nelson et al, 1999)
Our studies found that the active drug AQ4 is found only in the perinuclear location, whereas the prodrug AQ4N. Banoxantrone (AQ4N) is located in the cytoplasm
AQ4, the active drug, is found in the perinuclear location whereas the prodrug AQ4N is located in the cytoplasm

Summary

Introduction

Cytochrome P450 (CYPs) constitute a large superfamily of enzymes that are haem-thiolate proteins with ubiquitous expression and distribution in diverse life forms including bacteria, fungi, plants and animals (Nelson et al, 1999). CYPs play an important role in carcinogen and anticancer drug biotransformation (Tang et al, 2015). 58 human cytochrome P450s (CYPs) have been identified to date. Most CYPs have been well characterized, and biological substrates have been identified for nearly 75% of all known CYPs. there remains 25% of CYPs called “orphan P450s” which little physiological function has clearly been identified. CYP2S1 is a gene coding for the Cytochrome P450 2S1 protein, which has been shown to metabolize AQ4N, an anticancer prodrug, under anoxic conditions (Xiao et al, 2011, Nishida et al, 2010). The epoxygenase activity of CYP2S1 is inhibited in vitro by miconazole and liarozole, an inhibitor of CYP26 and CYP2S1 (Fromel et al, 2013).

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Conclusion