Mechanism-Based Inactivation of Cytochrome P450 Enzymes: Chemical Mechanisms, Structure-Activity Relationships and Relationship to Clinical Drug-Drug Interactions and Idiosyncratic Adverse Drug Reactions

Heme is central to functions of many biologically important enzymes (hemoproteins). It is an assembly of four porphyrin rings joined through methylene bridges with a central Fe (II). Heme is present in all cells, and its synthesis and degradation balance its amount in the cell. The deregulations of heme networks and incorporation in hemoproteins lead to pathogenic state. This article addresses the detailed structure, biosynthesis, degradation, and transportation associated afflictions to heme. The article is followed by its roles in various diseased conditions where it is produced mainly as the cause of increased hemolysis. It manifests the symptoms in diseases as it is a pro-oxidant, pro-inflammatory and pro-hemolytic agent. We have also discussed the genetic defects that tampered with the biosynthesis, degradation, and transportation of heme. In addition, a brief about the largest hemoprotein group of enzymes- Cytochrome P450 (CYP450) has been discussed with its roles in drug metabolism.

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Importance of cytochrome P450 (CYP450) in adverse drug reactions due to drug–drug interactions: a PharmacoVigilance study in France

European Journal of Clinical Pharmacology ◽

10.1007/s00228-012-1394-3 ◽

2012 ◽

Vol 69 (4) ◽

pp. 885-888 ◽

Cited By ~ 17

Author(s):

Anne Charlotte Danton ◽

François Montastruc ◽

Agnès Sommet ◽

Geneviève Durrieu ◽

Haleh Bagheri ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interactions ◽

Adverse Drug Reactions ◽

Drug Reactions

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Mechanism-Based Inactivation (MBI) of Cytochrome P450 Enzymes: Structure–Activity Relationships and Discovery Strategies To Mitigate Drug–Drug Interaction Risks

Journal of Medicinal Chemistry ◽

10.1021/jm300065h ◽

2012 ◽

Vol 55 (11) ◽

pp. 4896-4933 ◽

Cited By ~ 113

Author(s):

Suvi T. M. Orr ◽

Sharon L. Ripp ◽

T. Eric Ballard ◽

Jaclyn L. Henderson ◽

Dennis O. Scott ◽

...

Keyword(s):

Cytochrome P450 ◽

Drug Interaction ◽

Cytochrome P450 Enzymes ◽

Structure Activity Relationships ◽

Structure Activity ◽

Drug Drug Interaction

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Cytochrome P450 Enzymes and Transporters Induced by Anti-Human Immunodeficiency Virus Protease Inhibitors in Human Hepatocytes: Implications for Predicting Clinical Drug Interactions

Drug Metabolism and Disposition ◽

10.1124/dmd.107.016089 ◽

2007 ◽

Vol 35 (10) ◽

pp. 1853-1859 ◽

Cited By ~ 98

Author(s):

Vaishali Dixit ◽

Niresh Hariparsad ◽

Fang Li ◽

Pankaj Desai ◽

Kenneth E. Thummel ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cytochrome P450 ◽

Drug Interactions ◽

Protease Inhibitors ◽

Human Hepatocytes ◽

Cytochrome P450 Enzymes ◽

Human Immunodeficiency Virus Protease ◽

Immunodeficiency Virus ◽

Clinical Drug

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Severe Adverse Drug Reactions to Quetiapine in Two Patients Carrying CYP2D6*4 Variants: A Case Report

International Journal of Molecular Sciences ◽

10.3390/ijms22126480 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6480

Author(s):

Céline K. Stäuble ◽

Markus L. Lampert ◽

Thorsten Mikoteit ◽

Martin Hatzinger ◽

Kurt E. Hersberger ◽

...

Keyword(s):

Cytochrome P450 ◽

Case Report ◽

Adverse Drug Reactions ◽

Active Metabolite ◽

Hepatic Metabolism ◽

Cytochrome P450 3A4 ◽

Drug Reactions ◽

Drug Induced ◽

Potential Impact ◽

Intermediate Metabolizer

We report two cases of patients who developed severe adverse drug reactions including persistent movement disorders, nausea, and vertigo during treatment with quetiapine at maximum daily doses ranging between 300 and 400 mg. The extensive hepatic metabolism of quetiapine is mainly attributed to cytochrome P450 3A4 (CYP3A4). However, there is recent evidence supporting the idea of CYP2D6 playing a role in the clearance of the quetiapine active metabolite norquetiapine. Interestingly, both patients we are reporting of are carriers of the CYP2D6*4 variant, predicting an intermediate metabolizer phenotype. Additionally, co-medication with a known CYP2D6 inhibitor and renal impairment might have further affected quetiapine pharmacokinetics. The herein reported cases could spark a discussion on the potential impact of a patient’s pharmacogenetic predisposition in the treatment with quetiapine. However, further studies are warranted to promote the adoption of pharmacogenetic testing for the prevention of drug-induced toxicities associated with quetiapine.

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