Altered cytochrome 2E1 and 3A P450-dependent drug metabolism in advanced ovarian cancer correlates to tumour-associated inflammation.
Adult
Aged
Aged, 80 and over
C-Reactive Protein
/ analysis
Caffeine
/ pharmacology
Chlorzoxazone
/ analogs & derivatives
Cytochrome P-450 Enzyme System
/ metabolism
Cytokines
/ blood
Dextromethorphan
/ pharmacology
Female
Humans
Inflammation
/ immunology
Middle Aged
Omeprazole
/ analogs & derivatives
Ovarian Neoplasms
/ blood
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
09 2019
09 2019
Historique:
received:
27
03
2018
revised:
10
05
2019
accepted:
16
05
2019
pubmed:
27
6
2019
medline:
15
9
2020
entrez:
26
6
2019
Statut:
ppublish
Résumé
Previous work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer-related inflammation on multiple CYP enzymes using a validated drug cocktail. Patients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C-reactive protein and cytokine analysis. CYP2E1 activity was markedly up-regulated in cancer (6-hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL-6, IL-8, and TNF-α. Repression of CYP3A correlated with raised levels of serum C-reactive protein, IL-6, IL-8, and TNF-α. CYP enzyme activity is differentially affected by the presence of tumour-associated inflammation, affecting particularly CYP2E1- and CYP3A-mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.
Sections du résumé
BACKGROUND AND PURPOSE
Previous work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer-related inflammation on multiple CYP enzymes using a validated drug cocktail.
EXPERIMENTAL APPROACH
Patients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C-reactive protein and cytokine analysis.
KEY RESULTS
CYP2E1 activity was markedly up-regulated in cancer (6-hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL-6, IL-8, and TNF-α. Repression of CYP3A correlated with raised levels of serum C-reactive protein, IL-6, IL-8, and TNF-α.
CONCLUSIONS AND IMPLICATIONS
CYP enzyme activity is differentially affected by the presence of tumour-associated inflammation, affecting particularly CYP2E1- and CYP3A-mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.
Identifiants
pubmed: 31236938
doi: 10.1111/bph.14776
pmc: PMC6715602
doi:
Substances chimiques
Cytokines
0
6-hydroxychlorzoxazone
1750-45-4
Caffeine
3G6A5W338E
Dextromethorphan
7355X3ROTS
omeprazole sulfone
76X040Z74O
C-Reactive Protein
9007-41-4
Cytochrome P-450 Enzyme System
9035-51-2
Chlorzoxazone
H0DE420U8G
Omeprazole
KG60484QX9
Types de publication
Controlled Clinical Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3712-3722Informations de copyright
© 2019 The British Pharmacological Society.
Références
J Biol Chem. 2015 Feb 6;290(6):3850-64
pubmed: 25533469
J Pharmacol Exp Ther. 2003 Mar;304(3):1048-54
pubmed: 12604681
Mol Pharmacol. 1993 Oct;44(4):707-15
pubmed: 8232220
Br J Pharmacol. 2017 Dec;174 Suppl 1:S272-S359
pubmed: 29055034
Pharmacol Ther. 2015 Aug;152:125-34
pubmed: 25976912
Clin Pharmacol Ther. 1994 Jun;55(6):649-60
pubmed: 8004881
J Pharm Pharmacol. 2006 Jan;58(1):51-61
pubmed: 16393464
Annu Rev Pharmacol Toxicol. 2006;46:123-49
pubmed: 16402901
Br J Clin Pharmacol. 2000 Dec;50(6):605-13
pubmed: 11136300
Br J Pharmacol. 2017 Dec;174 Suppl 1:S208-S224
pubmed: 29055032
J Clin Oncol. 2002 Jul 15;20(14):3122-9
pubmed: 12118026
Br J Clin Pharmacol. 1997 Jun;43(6):627-32
pubmed: 9205823
Annu Rev Pharmacol Toxicol. 1998;38:389-430
pubmed: 9597161
J Biol Chem. 1995 Dec 15;270(50):29632-5
pubmed: 8530344
Cell. 2011 Mar 4;144(5):646-74
pubmed: 21376230
J Pharmacol Exp Ther. 2005 Feb;312(2):841-8
pubmed: 15456840
Mol Cell Biol. 1990 Sep;10(9):4495-505
pubmed: 2388615
J Pharm Biomed Anal. 2011 Jan 25;54(2):387-94
pubmed: 20926215
J Gastroenterol. 1994 Aug;29(4):423-9
pubmed: 7951851
Expert Rev Clin Pharmacol. 2012 Jan;5(1):69-89
pubmed: 22142160
J Clin Pharmacol. 2005 Jun;45(6):666-73
pubmed: 15901748
Ann Oncol. 2007 Jan;18(1):168-172
pubmed: 17060489
Clin Pharmacol Ther. 2018 Feb;103(2):271-280
pubmed: 29063606
Lancet Oncol. 2005 Oct;6(10):780-9
pubmed: 16198984
Anticancer Res. 1999 Mar-Apr;19(2B):1427-32
pubmed: 10365118
Nucleic Acids Res. 2018 Jan 4;46(D1):D1091-D1106
pubmed: 29149325
Annu Rev Pharmacol Toxicol. 1999;39:1-17
pubmed: 10331074
Nature. 2006 Apr 20;440(7087):1073-7
pubmed: 16625200
Biochem Biophys Res Commun. 1987 Feb 13;142(3):1077-83
pubmed: 3827895
J Chromatogr B Analyt Technol Biomed Life Sci. 2012 May 1;895-896:56-64
pubmed: 22483397
Drug Metab Dispos. 2007 Sep;35(9):1687-93
pubmed: 17576808
Mol Pharmacol. 1996 Nov;50(5):1065-72
pubmed: 8913336
Eur J Cancer. 2008 Jan;44(2):251-6
pubmed: 18155897
Biochem Biophys Res Commun. 2000 Aug 11;274(3):707-13
pubmed: 10924340
Drug Metab Dispos. 2007 Jan;35(1):1-8
pubmed: 17020953
J Clin Invest. 1994 Dec;94(6):2209-14
pubmed: 7989576
Clin Pharmacol Ther. 1997 Oct;62(4):365-76
pubmed: 9357387
Clin Cancer Res. 2000 Jul;6(7):2702-6
pubmed: 10914713
Clin Cancer Res. 2011 May 15;17(10):3170-80
pubmed: 21498392
Physiol Rev. 1997 Apr;77(2):517-44
pubmed: 9114822
Clin Pharmacol Ther. 2009 Apr;85(4):434-8
pubmed: 19212314
Br J Cancer. 2014 Dec 9;111(12):2287-96
pubmed: 25333344
Mol Pharmacol. 2004 Feb;65(2):279-81
pubmed: 14742668
Cancer Res. 1992 Jun 15;52(12):3317-22
pubmed: 1596890
Toxicol Lett. 2010 Sep 1;197(3):219-26
pubmed: 20538049
J Chromatogr B Analyt Technol Biomed Life Sci. 2002 Nov 25;780(2):459-65
pubmed: 12401374
Clin Pharmacol Ther. 2014 Oct;96(4):449-57
pubmed: 24987833
Clin Pharmacol Ther. 2004 Dec;76(6):618-27
pubmed: 15592333
Br J Cancer. 2002 Jul 29;87(3):277-80
pubmed: 12177794
Pharm Res. 2013 Sep;30(9):2270-8
pubmed: 23604979
J Biol Chem. 2006 Jun 30;281(26):17882-9
pubmed: 16608838
Toxicol Appl Pharmacol. 1984 May;73(3):423-31
pubmed: 6719461
J Card Fail. 2002 Oct;8(5):315-9
pubmed: 12411982
Clin Cancer Res. 2006 Dec 15;12(24):7492-7
pubmed: 17189422
Clin Pharmacol Ther. 2003 Dec;74(6):555-68
pubmed: 14663458
Clin Cancer Res. 2004 Dec 15;10(24):8341-50
pubmed: 15623611
Am J Gastroenterol. 1996 Jul;91(7):1417-22
pubmed: 8678006
Crit Rev Oncol Hematol. 2018 Jul;127:91-104
pubmed: 29891116
Br J Pharmacol. 2019 Sep;176(18):3712-3722
pubmed: 31236938
Lancet Oncol. 2003 Apr;4(4):224-32
pubmed: 12681266