Skip to main content

Research Repository

Advanced Search

CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity

Sonawane, Vinay R.; Mohd Usman, Mohd Siddique; Gatchie, Linda; Williams, Ibidapo Stephen; Bharate, Sandip B.; Jayaprakash, Venkatesan; Sinha, Barij N.; Chaudhuri, Bhabatosh

Authors

Vinay R. Sonawane

Mohd Siddique Mohd Usman

Linda Gatchie

Ibidapo Williams Ibidapo.Williams@uwe.ac.uk
Research Fellow- Cell Cultural Monitoring Technology

Sandip B. Bharate

Venkatesan Jayaprakash

Barij N. Sinha

Bhabatosh Chaudhuri



Abstract

Microsomal cytochrome P450 (CYP) enzymes, isolated from recombinant bacterial/insect/yeast cells, are extensively used for drug metabolism studies. However, they may not always portray how a developmental drug would behave in human cells with intact intracellular transport mechanisms. This study emphasizes the usefulness of human HEK293 kidney cells, grown in ‘suspension’ for expression of CYPs, in finding potent CYP1A1/CYP1B1 inhibitors, as possible anticancer agents. With live cell-based assays, quinazolinones 9i/9b were found to be selective CYP1A1/CYP1B1 inhibitors with IC50 values of 30/21 nM, and > 150-fold selectivity over CYP2/3 enzymes, whereas they were far less active using commercially-available CYP1A1/CYP1B1 microsomal enzymes (IC50, >10/1.3–1.7 μM). Compound 9i prevented CYP1A1-mediated benzo[a]pyrene-toxicity in normal fibroblasts whereas 9b completely reversed cisplatin resistance in PC-3/prostate, COR-L23/lung, MIAPaCa-2/pancreatic and LS174T/colon cancer cells, underlining the human-cell-assays' potential. Our results indicate that the most potent CYP1A1/CYP1B1 inhibitors would not have been identified if one had relied merely on microsomal enzymes.

Citation

Williams, I. S., Sonawane, V. R., Mohd Usman, M. S., Gatchie, L., .Bharate, S. B., Jayaprakash, V., …Chaudhuri, B. (2019). CYP enzymes, expressed within live human suspension cells, are superior to widely-used microsomal enzymes in identifying potent CYP1A1/CYP1B1 inhibitors: Identification of quinazolinones as CYP1A1/CYP1B1 inhibitors that efficiently reverse B[a]P toxicity and cisplatin resistance. European Journal of Pharmaceutical Sciences, 131, 177-194. https://doi.org/10.1016/j.ejps.2019.02.016

Journal Article Type Article
Acceptance Date Feb 12, 2019
Online Publication Date Feb 15, 2019
Publication Date Apr 1, 2019
Journal European Journal of Pharmaceutical Sciences
Print ISSN 0928-0987
Electronic ISSN 1879-0720
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 131
Pages 177-194
DOI https://doi.org/10.1016/j.ejps.2019.02.016
Keywords microsomal CYP450 enzymes, cisplatin resistance, CYP1A1 inhibitors,
CYP1A1-mediated benzo[a]pyrene toxicity, CYP1B1 inhibitors, hard to metabolize medications, live CYP-expressing human cells
Public URL https://uwe-repository.worktribe.com/output/849457
Publisher URL https://doi.org/10.1016/j.ejps.2019.02.016
Related Public URLs https://www.sciencedirect.com/science/article/pii/S0928098719300697?via%3Dihub