Zotepine

Identification

Generic Name
Zotepine
DrugBank Accession Number
DB09225
Background

Zotepine, with the formula (2-chloro-11-(2-dimethyl-amino-ethoxy)-dibenzo thiepin, is a neuroleptic drug. It was designed and synthesized by Fujisawa Pharmaceutical Co Ltd.1 It has been used as an antipsychotic in Japan, India and some places in Europe like UK and Germany since 1980's.2 Zotepine was never approved by the FDA. In 1993, it was classified as inactive drug substance (Status I, Type II) and in 1995 the FDA studied the manufacturing procedures of Zotepine tablets in Germany, but the status remained inactive.9 When the analysis of antipsychotics was retaken in 2016 by the FDA, zotepine did not reach the threshold effect to be further studied.10. In the EMA, by 2015 it was under pharmacovigilance studies for the potential treatment of acute renal failure.11

Type
Small Molecule
Groups
Approved, Investigational, Withdrawn
Structure
Weight
Average: 331.86
Monoisotopic: 331.0797631
Chemical Formula
C18H18ClNOS
Synonyms
  • Zotepina
  • Zotepine

Pharmacology

Indication

Zotepine, like other atypical antipsychotics, is considered as the first-line treatment in newly diagnosed schizophrenia. It is usually thought to be an option of choice for managing acute schizophrenic episodes when discussion with the patient is not possible. Zotepine, as an atypical antipsychotic, is used in patients who are suffering unacceptable side effects from conventional antipsychotics or in relapse patients that were inadequately controlled.7

It is important to consider that the indications stated above are related to atypical antipsychotics, that zotepine is not currently FDA, Canada or EMA approved and that studies have not shown any additional benefit when compared with other approved atypical antipsychotics.2

Schizophrenia is a chronic and severe mental disorder that affects how a person thinks, feels and behaves. It is usually marked for a loose reality perspective delineated by hallucinations, delusions and thought and movement disorders.12

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Contraindications & Blackbox Warnings
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Pharmacodynamics

In preclinical studies, zotepine is characterized by the presence of a strong antiserotonergic activity when compared with other neuroleptic drugs. It has also been reported to present elevations in the seizure threshold in the amygdaloid nucleus.1 When zotepine's effects were analyzed by electroencephalography, it was noted a typical response of a low-potency neuroleptics of the sedative type. Administration of zotepine has shown improvements in numerical movements and complex reaction. These effects tend to be accompanied by increases in pulse rate, increase in prolactin levels and some typical neuroleptic side effects.3,4

Mechanism of action

Zotepine is a dopamine antagonist that has a high affinity for D1- and D2-like receptors. It presents a strong antagonism for several serotonin receptors, such as 5-HT2a, 5-HT2c, 5-HT6 and 5-HT7. Zotepine activities are also related to the inhibition of noradrenaline reuptake and serotonergic activity. All these effects allow zotepine to improve the negative and cognitive symptoms of schizophrenia.8

TargetActionsOrganism
AD(1) dopamine receptor
antagonist
Humans
AD(2) dopamine receptor
antagonist
Humans
A5-hydroxytryptamine receptor 2A
antagonist
Humans
A5-hydroxytryptamine receptor 7
antagonist
Humans
ASodium-dependent noradrenaline transporter
antagonist
Humans
ASodium-dependent serotonin transporter
antagonist
Humans
U5-hydroxytryptamine receptor 6
antagonist
Humans
Absorption

Preclinical pharmacokinetic studies have shown a dose-dependent increase in plasma levels with a tmax between 2-4 hours and Cmax from 6.9-19.6 ng/ml when administered in a dose of 25-100 mg of zotepine. The maximum concentration peaks and slow declines thereafter.4 When administered orally in preclinical studies, zotepine was proven to be absorbed rapidly and almost completely from the gastrointestinal tract.The unchanged drug and metabolites are rapidly distributed to the tissues.5

Volume of distribution

The apparent volume of distribution of zotepine is 109 L/kg.6

Protein binding

Plasma protein binding of zotepine and its major active metabolite norzotepine account for 97% of the administered dose.13

Metabolism

Zotepine is well metabolized in the body, it actually undergoes extensive first-pass metabolism to the metabolite norzotepine and several inactive metabolites. The main enzymes involved in zotepine metabolism are CYP1A2 and CYP3A4.13 Some of the main metabolic pathways include N-demethylation and oxygenation of N or S atoms, hydroxylation of the aromatic ring and consecutive conjugation.5

Hover over products below to view reaction partners

Route of elimination

Only small amounts of the unchanged zotepine are excreted in the urine and fecal excretion through the bile is the main route of elimination of both the unchanged drug and its metabolites.5

Half-life

The half-life of zotepine is reported to be of 21 hours.6

Clearance

The apparent oral clearance of zotepine is 4.6 mg/h.kg.6

Adverse Effects
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Toxicity

The use of zotepine has been vastly related to ongoing extrapyramidal side effects and it has been reported to be poorly tolerated by the patients.1,2

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
1,2-BenzodiazepineThe risk or severity of CNS depression can be increased when Zotepine is combined with 1,2-Benzodiazepine.
AbametapirThe serum concentration of Zotepine can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Zotepine can be increased when combined with Abatacept.
AbirateroneThe serum concentration of Zotepine can be increased when it is combined with Abiraterone.
AcenocoumarolThe metabolism of Zotepine can be decreased when combined with Acenocoumarol.
Food Interactions
Not Available

Products

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International/Other Brands
Losizopilon / Zoleptil

Categories

ATC Codes
N05AX11 — Zotepine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as dibenzothiepins. These are compounds containing a dibenzothiepin moiety, which consists of two benzene connected by a thiepine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Benzothiepins
Sub Class
Dibenzothiepins
Direct Parent
Dibenzothiepins
Alternative Parents
Diarylthioethers / Benzenoids / Aryl chlorides / Trialkylamines / Organopnictogen compounds / Organooxygen compounds / Organochlorides / Hydrocarbon derivatives
Substituents
Amine / Aromatic heteropolycyclic compound / Aryl chloride / Aryl halide / Aryl thioether / Benzenoid / Diarylthioether / Dibenzothiepin / Hydrocarbon derivative / Organic nitrogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
tertiary amino compound, dibenzothiepine (CHEBI:32316)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
U29O83JAZW
CAS number
26615-21-4
InChI Key
HDOZVRUNCMBHFH-UHFFFAOYSA-N
InChI
InChI=1S/C18H18ClNOS/c1-20(2)9-10-21-16-11-13-5-3-4-6-17(13)22-18-8-7-14(19)12-15(16)18/h3-8,11-12H,9-10H2,1-2H3
IUPAC Name
[2-({6-chloro-2-thiatricyclo[9.4.0.0³,⁸]pentadeca-1(15),3,5,7,9,11,13-heptaen-9-yl}oxy)ethyl]dimethylamine
SMILES
CN(C)CCOC1=CC2=CC=CC=C2SC2=CC=C(Cl)C=C12

References

General References
  1. Satoh H, Shimomura K, Mori J: Effect of zotepine on afterdischarge induced by electrical stimulation of amygdaloid nucleus in rats. Jpn J Pharmacol. 1982 Apr;32(2):381-3. [Article]
  2. Bishnoi RJ, Jhanwar VG: Tolerability of zotepine in Indian patients: Preliminary experience. Ind Psychiatry J. 2010 Jul;19(2):130-1. doi: 10.4103/0972-6748.90345. [Article]
  3. Saletu B, Grunberger J, Linzmayer L, Anderer P: Comparative placebo-controlled pharmacodynamic studies with zotepine and clozapine utilizing pharmaco-EEG and psychometry. Pharmacopsychiatry. 1987 Feb;20(1 Spec No):12-27. doi: 10.1055/s-2007-1017125. [Article]
  4. Saletu B, Grunberger J, Anderer P, Chwatal K: [Relation between blood levels and average quantitative EEG and psychometrically assessed pharmacodynamic changes following zotepine]. Fortschr Neurol Psychiatr. 1991 Sep;59 Suppl 1:45-55. doi: 10.1055/s-2007-1000735. [Article]
  5. Noda K, Suzuki A, Okui M, Noguchi H, Nishiura M, Nishiura N: Pharmacokinetics and metabolism of 2-chloro-11-(2-dimethylaminoethoxy)-dibenzo[b,f]thiepine (zotepine) in rat, mouse, dog and man. Arzneimittelforschung. 1979;29(10):1595-600. [Article]
  6. Tanaka O, Kondo T, Otani K, Yasui N, Tokinaga N, Kaneko S: Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects. Ther Drug Monit. 1998 Feb;20(1):117-9. [Article]
  7. Wright P. and O'Neill M. (2012). Core psychiatry (3rd ed.). Elsevier.
  8. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
  9. FDA Submission [Link]
  10. FDA antipsychotics [Link]
  11. EMA reports [Link]
  12. NIMH [Link]
  13. Zotepine monograph [Link]
KEGG Drug
D01321
PubChem Compound
5736
PubChem Substance
310265131
ChemSpider
5534
BindingDB
35255
RxNav
40003
ChEBI
32316
ChEMBL
CHEMBL285802
ZINC
ZINC000000002264
PDBe Ligand
ZOT
Wikipedia
Zotepine
PDB Entries
6a94
MSDS
Download (52.4 KB)

Clinical Trials

Clinical Trials
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PhaseStatusPurposeConditionsCountStart DateWhy Stopped100+ additional columns
Not AvailableCompletedNot AvailableBipolar Disorder (BD)1somestatusstop reasonjust information to hide
4TerminatedTreatmentDelirium1somestatusstop reasonjust information to hide
4TerminatedTreatmentSchizophrenia1somestatusstop reasonjust information to hide

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, coatedOral50 mg
Tablet, film coatedOral25 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)90ºC'MSDS'
boiling point (°C)478.4ºC'MSDS'
water solubilityPoorly soluble Patent US6239165
logP4.25'MSDS'
Predicted Properties
PropertyValueSource
Water Solubility0.000777 mg/mLALOGPS
logP4.74ALOGPS
logP4.51Chemaxon
logS-5.6ALOGPS
pKa (Strongest Basic)8.92Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count2Chemaxon
Hydrogen Donor Count0Chemaxon
Polar Surface Area12.47 Å2Chemaxon
Rotatable Bond Count4Chemaxon
Refractivity97.61 m3·mol-1Chemaxon
Polarizability36.21 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-9000000000-7a5abea6a8b8bb055491
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0094000000-7d13f2545c6f7e7b1ef8
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-9002000000-8381383fe7eee311ebe9
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0091000000-912a1326874638777318
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-00di-9010000000-39c766fc0caa99a6f330
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0a4i-0090000000-48c19788721254a01e03
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-169.81741
predicted
DeepCCS 1.0 (2019)
[M+H]+172.1754
predicted
DeepCCS 1.0 (2019)
[M+Na]+178.26855
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein group
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Dopamine receptor whose activity is mediated by G proteins which activate adenylyl cyclase
Specific Function
arrestin family protein binding

Components:
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Dopamine receptor whose activity is mediated by G proteins which inhibit adenylyl cyclase (PubMed:21645528). Positively regulates postnatal regression of retinal hyaloid vessels via suppression of VEGFR2/KDR activity, downstream of OPN5 (By similarity)
Specific Function
dopamine binding
Gene Name
DRD2
Uniprot ID
P14416
Uniprot Name
D(2) dopamine receptor
Molecular Weight
50618.91 Da
References
  1. Suzuki H, Gen K, Inoue Y: Comparison of the anti-dopamine D(2) and anti-serotonin 5-HT(2A) activities of chlorpromazine, bromperidol, haloperidol and second-generation antipsychotics parent compounds and metabolites thereof. J Psychopharmacol. 2013 Apr;27(4):396-400. doi: 10.1177/0269881113478281. Epub 2013 Feb 20. [Article]
  2. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:1330647, PubMed:18703043, PubMed:19057895, PubMed:21645528, PubMed:22300836, PubMed:35084960, PubMed:38552625). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and lysergic acid diethylamide (LSD) (PubMed:28129538, PubMed:35084960). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:28129538, PubMed:35084960). HTR2A is coupled to G(q)/G(11) G alpha proteins and activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers that modulate the activity of phosphatidylinositol 3-kinase and promote the release of Ca(2+) ions from intracellular stores, respectively (PubMed:18703043, PubMed:28129538, PubMed:35084960). Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways (PubMed:28129538, PubMed:35084960). Affects neural activity, perception, cognition and mood (PubMed:18297054). Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction (By similarity)
Specific Function
1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35714614, PubMed:8226867). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35714614, PubMed:8226867). HTR7 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:35714614)
Specific Function
G protein-coupled serotonin receptor activity
Gene Name
HTR7
Uniprot ID
P34969
Uniprot Name
5-hydroxytryptamine receptor 7
Molecular Weight
53554.43 Da
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Mediates sodium- and chloride-dependent transport of norepinephrine (also known as noradrenaline) (PubMed:2008212, PubMed:8125921). Can also mediate sodium- and chloride-dependent transport of dopamine (PubMed:11093780, PubMed:8125921)
Specific Function
actin binding
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Antagonist
General Function
Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle. Transports serotonin across the plasma membrane from the extracellular compartment to the cytosol thus limiting serotonin intercellular signaling (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Essential for serotonin homeostasis in the central nervous system. In the developing somatosensory cortex, acts in glutamatergic neurons to control serotonin uptake and its trophic functions accounting for proper spatial organization of cortical neurons and elaboration of sensory circuits. In the mature cortex, acts primarily in brainstem raphe neurons to mediate serotonin uptake from the synaptic cleft back into the pre-synaptic terminal thus terminating serotonin signaling at the synapse (By similarity). Modulates mucosal serotonin levels in the gastrointestinal tract through uptake and clearance of serotonin in enterocytes. Required for enteric neurogenesis and gastrointestinal reflexes (By similarity). Regulates blood serotonin levels by ensuring rapid high affinity uptake of serotonin from plasma to platelets, where it is further stored in dense granules via vesicular monoamine transporters and then released upon stimulation (PubMed:17506858, PubMed:18317590). Mechanistically, the transport cycle starts with an outward-open conformation having Na1(+) and Cl(-) sites occupied. The binding of a second extracellular Na2(+) ion and serotonin substrate leads to structural changes to outward-occluded to inward-occluded to inward-open, where the Na2(+) ion and serotonin are released into the cytosol. Binding of intracellular K(+) ion induces conformational transitions to inward-occluded to outward-open and completes the cycle by releasing K(+) possibly together with a proton bound to Asp-98 into the extracellular compartment. Na1(+) and Cl(-) ions remain bound throughout the transport cycle (PubMed:10407194, PubMed:12869649, PubMed:21730057, PubMed:27049939, PubMed:27756841, PubMed:34851672). Additionally, displays serotonin-induced channel-like conductance for monovalent cations, mainly Na(+) ions. The channel activity is uncoupled from the transport cycle and may contribute to the membrane resting potential or excitability (By similarity)
Specific Function
actin filament binding
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Antagonist
General Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen (PubMed:35714614, PubMed:36989299, PubMed:37327704, PubMed:8522988). Also has a high affinity for tricyclic psychotropic drugs (By similarity). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors (PubMed:35714614). HTR6 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity (PubMed:35714614, PubMed:37327704). Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity (By similarity). Is an activator of mTOR signaling (PubMed:23027611)
Specific Function
G protein-coupled serotonin receptor activity
Gene Name
HTR6
Uniprot ID
P50406
Uniprot Name
5-hydroxytryptamine receptor 6
Molecular Weight
46953.625 Da
References
  1. Macdonald G. and Bartolome J.M. (2010). Progress in Medicinal Chemistry. Lawton and Witty.

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576, PubMed:9435160). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable)
Specific Function
aromatase activity
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58406.915 Da
References
  1. Shiraga T, Kaneko H, Iwasaki K, Tozuka Z, Suzuki A, Hata T: Identification of cytochrome P450 enzymes involved in the metabolism of zotepine, an antipsychotic drug, in human liver microsomes. Xenobiotica. 1999 Mar;29(3):217-29. doi: 10.1080/004982599238623 . [Article]
  2. Zotepine monograph [File]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
Specific Function
1,8-cineole 2-exo-monooxygenase activity
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Zotepine monograph [Link]

Drug created at October 22, 2015 20:22 / Updated at February 21, 2021 18:52