Metamizole is a moderate cytochrome P450 inducer via the constitutive androstane receptor and a weak inhibitor of CYP1A2

Vorozole and letrozole are third-generation aromatase (cytochrome P450 19A1) inhibitors. [11C]-Vorozole can be used as a radiotracer for aromatase in living animals but when administered by IV, it collects in the liver. Pretreatment with letrozole does not affect the binding of vorozole in the liver. In search of finding the protein responsible for the accumulation of vorozole in the liver, fluorometric high-throughput screening assays were used to test the inhibitory capability of vorozole and letrozole on a series of liver cytochrome P450s (CYP1A1, CYP1A2, CYP2A6, and CYP3A4). It was determined that vorozole is a potent inhibitor of CYP1A1 (IC50 = 0.469 μM) and a moderate inhibitor of CYP2A6 and CYP3A4 (IC50 = 24.4 and 98.1 μM, resp.). Letrozole is only a moderate inhibitor of CYP1A1 and CYP2A6 (IC50 = 69.8 and 106 μM) and a very weak inhibitor of CYP3A4 (<10% inhibition at 1 mM). Since CYP3A4 makes up the majority of the CYP content found in the human liver, and vorozole inhibits it moderately well but letrozole does not, CYP3A4 is a good candidate for the protein that [11C]-vorozole is binding to in the liver.

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The Most Severe Somatic Disorders Treated with Excitaloprim

European Psychiatry ◽

10.1016/s0924-9338(09)70737-0 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

S. Kaludjerovic

Keyword(s):

Cytochrome P450 ◽

Major Depression ◽

List Type ◽

Weak Inhibitor ◽

Liver Cytochrome ◽

Icd 10 ◽

Persistent Depression ◽

Somatic Disorders ◽

The Moment ◽

Almost All

Almost all of patients treated for cancers, experience episodes of persistent depression. Which moment is the most terrible? The moment patients hear their diagnosis,or time suffer while getting chemotherapy?The time on controls tumor markers or when their relatives give up on them? When mirror reflects damaged body and face. Or felt useless in the presence of their children?•diagnosis of cancers C00,E05 are difficult to accept, and go hand in hand with major depression F33/ according to ICD-10.•why excitaloprim as choice?Patients age 27 to 37 need antidepressant with pharmacokinetic superiority. Excitaloprim works faster than any other antidepressant, and it is strong, thanks to its dual serotonergic bonding on primar part as well as alosteric part bonding. It is weak inhibitor of the well defined liver cytochrome P450 isoenzym, CYP2D6., EEg .EKG is ok, so its safe drug/.In this study, I followed the results of excitaloprim treatment on 30 patients (20 females, 10 males).During 2 months, 20 patients were diagnosed with cancer (mostly colon and breast). All this patients have already been operated. Some have anus praeternaturalis.Other patients have AIDSinitial phase, and autoimmune dg/On Hamilton scale, 45, points, MADRS on 10 items, 40, on Becks scale 65.Zung self rating index o,6. In this project, patients without children were much more suicidal.Cancer patients got 20 mg excitaloprim pro die, other 10 mg pro die. After 2 mothsscales showed statistically important improvements despite severity.

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Regulation of Cytochrome P450 2a5 by Artemisia capillaris and 6,7-Dimethylesculetin in Mouse Hepatocytes

Frontiers in Pharmacology ◽

10.3389/fphar.2021.730416 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sangsoo Daniel Kim ◽

Larry Morgan ◽

Elyse Hargreaves ◽

Xiaoying Zhang ◽

Zhihui Jiang ◽

...

Keyword(s):

Cytochrome P450 ◽

Nuclear Translocation ◽

Constitutive Androstane Receptor ◽

Elevated Serum ◽

Regulatory Control ◽

Herbal Remedies ◽

Luciferase Reporter ◽

Artemisia Capillaris ◽

Primary Mouse ◽

Mouse Hepatocytes

Jaundice is a potentially fatal condition resulting from elevated serum bilirubin levels. For centuries, herbal remedies containing Artemisia capillaris Thunb. including the compound 6,7-dimethylesculetin (DE) have been used in Asia to prevent and treat jaundice in neonates. DE activates an important regulator of bilirubin metabolism, the constitutive androstane receptor (CAR), and increases bilirubin clearance. In addition, murine cytochrome P450 2a5 (Cyp2a5) is known to be involved in the oxidative metabolism of bilirubin. Moreover, treatment of mice with phenobarbital, a known inducer of both CAR and Cyp2a5, increases expression of Cyp2a5 suggesting a potential relationship between CAR and Cyp2a5 expression. The aim of this study is to investigate the influence of Artemisia capillaris and DE on the expression and regulatory control of Cyp2a5 and the potential involvement of CAR. Treatment of mouse hepatocytes in primary culture with DE (50 μM) significant increased Cyp2a5 mRNA and protein levels. In mice, Artemisia capillaris and DE treatment also increased levels of hepatic Cyp2a5 protein. Luciferase reporter assays showed that CAR increases Cyp2a5 gene transcription through a CAR response element in the Cyp2a5 gene promoter. Moreover, DE caused nuclear translocation of CAR in primary mouse hepatocytes and increased Cyp2a5 transcription in the presence of CAR. These results identify a potential CAR-mediated mechanism by which DE regulates Cyp2a5 gene expression and suggests that DE may enhance bilirubin clearance by increasing Cyp2a5 levels. Understanding this process could provide an opportunity for the development of novel therapies for neonatal and other forms of jaundice.

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Comparative studies on the effects of sodium phenobarbital and two other constitutive androstane receptor (CAR) activators on induction of cytochrome P450 enzymes and replicative DNA synthesis in cultured hepatocytes from wild type and CAR knockout rats

Toxicology ◽

10.1016/j.tox.2020.152394 ◽

2020 ◽

Vol 433-434 ◽

pp. 152394

Author(s):

Manuela Goettel ◽

Ivana Fegert ◽

Naveed Honarvar ◽

Audrey Vardy ◽

Corinne Haines ◽

...

Keyword(s):

Cytochrome P450 ◽

Dna Synthesis ◽

Comparative Studies ◽

Constitutive Androstane Receptor ◽

Cultured Hepatocytes ◽

Wild Type ◽

Cytochrome P450 Enzymes ◽

Sodium Phenobarbital

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Cytochrome P450 Gene Regulation: Reporter Assays to Assess Direct and Indirect Activation of Constitutive Androstane Receptor (CAR, NR1I3)

Methods in Pharmacology and Toxicology - Cytochrome P450 ◽

10.1007/978-1-0716-1542-3_11 ◽

2021 ◽

pp. 175-192

Author(s):

Marija Pinne ◽

Judy L. Raucy

Keyword(s):

Gene Regulation ◽

Cytochrome P450 ◽

Constitutive Androstane Receptor ◽

Cytochrome P450 Gene ◽

P450 Gene ◽

Reporter Assays ◽

Indirect Activation

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Octachlorostyrene induces cytochrome P450, UDP-glucuronosyltransferase, and sulfotransferase via the aryl hydrocarbon receptor and constitutive androstane receptor

Toxicology Letters ◽

10.1016/j.toxlet.2010.03.382 ◽

2010 ◽

Vol 196 ◽

pp. S107 ◽

Cited By ~ 2

Author(s):

Y. Yanagiba

Keyword(s):

Cytochrome P450 ◽

Aryl Hydrocarbon Receptor ◽

Constitutive Androstane Receptor ◽

Aryl Hydrocarbon ◽

Udp Glucuronosyltransferase

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Antimalarial Artemisinin Drugs Induce Cytochrome P450 and MDR1 Expression by Activation of Xenosensors Pregnane X Receptor and Constitutive Androstane Receptor

Molecular Pharmacology ◽

10.1124/mol.104.009019 ◽

2005 ◽

Vol 67 (6) ◽

pp. 1954-1965 ◽

Cited By ~ 156

Author(s):

Oliver Burk ◽

Katja A. Arnold ◽

Andreas K. Nussler ◽

Elke Schaeffeler ◽

Ekaterina Efimova ◽

...

Keyword(s):

Cytochrome P450 ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Mdr1 Expression

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Octachlorostyrene Induces Cytochrome P450, UDP-glucuronosyltransferase, and Sulfotransferase via the Aryl Hydrocarbon Receptor and Constitutive Androstane Receptor

Toxicological Sciences ◽

10.1093/toxsci/kfp130 ◽

2009 ◽

Vol 111 (1) ◽

pp. 19-26 ◽

Cited By ~ 13

Author(s):

Yukie Yanagiba ◽

Yuki Ito ◽

Michihiro Kamijima ◽

Frank J. Gonzalez ◽

Tamie Nakajima

Keyword(s):

Cytochrome P450 ◽

Aryl Hydrocarbon Receptor ◽

Constitutive Androstane Receptor ◽

Aryl Hydrocarbon ◽

Udp Glucuronosyltransferase

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Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway

Biochemical Journal ◽

10.1042/bj20080740 ◽

2008 ◽

Vol 417 (1) ◽

pp. 43-58 ◽

Cited By ~ 52

Author(s):

Robert D. Finn ◽

Colin J. Henderson ◽

Claire L. Scott ◽

C. Roland Wolf

Keyword(s):

Cytochrome P450 ◽

Fatty Acid ◽

Unsaturated Fatty Acid ◽

Unsaturated Fatty Acids ◽

Constitutive Androstane Receptor ◽

Pregnane X Receptor ◽

Xenobiotic Metabolism ◽

Environmental Chemicals ◽

Liver Growth ◽

P450 Expression

The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes. We demonstrate that P450 induction, liver growth and hepatic triacylglycerol (triglyceride) homoeostasis are intimately linked and provide evidence that the observed phenotypes result from hepatic accumulation of unsaturated fatty acids, which mediate these phenotypes by activation of the nuclear receptor CAR (constitutive androstane receptor) and, to a lesser degree, PXR (pregnane X receptor). To our knowledge this is the first direct evidence that P450s play a major role in controlling unsaturated fatty acid homoeostasis via CAR. The regulation of P450s involved in xenobiotic metabolism by this mechanism has potentially significant implications for individual responses to drugs and environmental chemicals.

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