Propranolol is a mechanism-based inhibitor of CYP2D and CYP2D6 in humanized CYP2D6-transgenic mice: Effects on activity and drug responses.
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
12
06
2019
revised:
16
08
2019
accepted:
13
09
2019
pubmed:
28
10
2019
medline:
22
6
2021
entrez:
25
10
2019
Statut:
ppublish
Résumé
Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours. Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied. Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.
Sections du résumé
BACKGROUND AND PURPOSE
Genetics and drug interactions contribute to large interindividual variation in human CYP2D6 activity. Here, we have characterized propranolol inhibition of human and mouse CYP2D using transgenic (TG) mice, which express both mouse CYP2D and human CYP2D6, and wild-type (WT) mice. Our purpose was to develop a method for in vivo manipulation of CYP2D6 enzyme activity which could be used to investigate the role of CYP2D6 in drug-induced behaviours.
EXPERIMENTAL APPROACH
Dextromethorphan metabolism to dextrorphan was used to measure CYP2D activity and to characterize propranolol inhibition in vitro and in vivo. Effects of propranolol pretreatment (24 hr) on serum levels of the CYP2D6 substrate haloperidol and haloperidol-induced catalepsy were also studied.
KEY RESULTS
Dextrorphan formation velocity in vitro was threefold higher in liver microsomes of TG compared to WT mice. Propranolol acted as a mechanism-based inhibitor (MBI), inactivating CYP2D in liver microsomes from TG and WT mice, and humans. Pretreatment (24 hr) of TG and WT mice with 20 mg·kg
CONCLUSIONS AND IMPLICATIONS
Propranolol was a potent MBI of dextrorphan formation in liver microsomes from TG and WT mice, and humans. The inhibition parameters in TG overlapped with those in WT mice and in humans. Inhibition of CYP2D with propranolol in vivo in TG and WT mice altered drug responses, allowing further investigation of variations in CYP2D6 on drug interactions and drug responses.
Identifiants
pubmed: 31648367
doi: 10.1111/bph.14884
pmc: PMC7012948
doi:
Substances chimiques
Cytochrome P-450 CYP2D6 Inhibitors
0
Propranolol
9Y8NXQ24VQ
Cytochrome P-450 CYP2D6
EC 1.14.14.1
Haloperidol
J6292F8L3D
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
701-712Subventions
Organisme : Campbell Family Mental Health Research Institute of the Centre for Addiction and Mental Health (CAMH)
Pays : International
Organisme : CIHR
ID : FDN 154294
Pays : Canada
Organisme : CIHR
ID : FRN 132557
Pays : Canada
Organisme : Canada Research Chair in Pharmacogenomics
Pays : International
Informations de copyright
© 2019 The British Pharmacological Society.
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