TITLE

Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

AUTHOR(S)
Shu-Feng Zhou
PUB. DATE
November 2009
SOURCE
Clinical Pharmacokinetics;2009, Vol. 48 Issue 11, p689
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (~2-4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes ~25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, β-adrenoceptor antagonists (β-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol.…
ACCESSION #
47637401

 

Related Articles

  • CYP2A6 genotypes and coumarin-oxidation phenotypes in a Thai population and their relationship to tobacco smoking. Mahavorasirikul, Wiratchanee; Tassaneeyakul, Wichittra; Satarug, Soisagwan; Reungweerayut, Ronnatrai; Na-Bangchang, Chacrin; Na-Bangchang, Kesara // European Journal of Clinical Pharmacology;Apr2009, Vol. 65 Issue 4, p377 

    To investigate the association between polymorphisms in the human CYP2A6 gene, CYP2A6 enzyme activity and the influence of cigarette smoking in a Thai population. Coumarin (5 mg capsule) was administered to 194 healthy Thai subjects. Genetic variation of the CYP2A6 gene was identified using PCR...

  • Recent Advances in Geriatric Psychopharmacology. Herrmann, Nathan; Tourigny-Rivard, Marie-France // Canadian Journal of Psychiatry;Jun1997 Supplement, Vol. 42, p3s 

    The article discusses various reports published within the issue, including one by Richard W. Shulman and Vural Özdemir on the role of cytochrome P450 system and the new field of pharmacogenetics, and another by Marie-France Tourigny-Rivard on the use of antidepressants in the elderly.

  • Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Dingemanse, J.; Schaarschmidt, D.; van Giersbergen, P.L.M.; Dingemanse, Jasper; Schaarschmidt, Dieter; van Giersbergen, Paul L M // Clinical Pharmacokinetics;Feb2003, Vol. 42 Issue 3, p293 

    Background: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4.Purpose: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate.Methods: Nine healthy male...

  • High Frequency of CYP1A1∗2C Allele in Brazilian Populations. Gaspar, Pedro A.; Kvitko, Katia; Papadópolis, Lidia G.; Hutz, Mara H.; Weimer, Tania A. // Human Biology;Apr2002, Vol. 74 Issue 2, p235 

    Investigates the genetic variability of the CYP1A1 I462V polymorphism in Brazilian populations. Analysis of CYP1A1 polymorphism; Characteristics of the CYP1A1 gene; Explanation for high frequency of the gene in the Brazilian populations; Components of phase I cytochrome P450 superfamily.

  • Genetic polymorphism of cytochrome P450 as a biomarker of susceptibility to environmental toxicity. Hong, Jun-Yan; Yang, Chung S. // Environmental Health Perspectives Supplements;Jun97 Supplement 4, Vol. 105, p759 

    Focuses on approaches and methods used in cytochrome P450 (CYP) genetic polymorphism studies. Phenotypic determination of CYP polymorphisms; Genetic basis of metabolic polymorphisms; Genotyping approach; CYP genetic polymorphism and cancer risk; Problems and perspectives.

  • A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants*. Sim, Sarah C.; Risinger, Carl; Dahl, Marja-Liisa; Aklillu, Eleni; Christensen, Magnus; Bertilsson, Leif; Ingelman-Sundberg, Magnus // Clinical Pharmacology & Therapeutics;Jan2006, Vol. 79 Issue 1, p103 

    Background and Objective: Many drugs, including proton pump inhibitors and certain antidepressants, are metabolized by the polymorphic cytochrome P450 (CYP) 2C19 enzyme. A significant portion of extensive metabolizers do not reach appropriate drug levels, and our objective was to investigate any...

  • The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder. Höfer, Peter; Schosser, Alexandra; Calati, Raffaella; Serretti, Alessandro; Massat, Isabelle; Kocabas, Neslihan; Konstantinidis, Anastasios; Linotte, Sylvie; Mendlewicz, Julien; Souery, Daniel; Zohar, Joseph; Juven-Wetzler, Alzbeta; Montgomery, Stuart; Kasper, Siegfried // European Archives of Psychiatry & Clinical Neuroscience;Aug2013, Vol. 263 Issue 5, p385 

    Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred...

  • Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study. Bonifacio, Alois; Groenhof, André; Keizers, Peter; Graaf, Chris; Commandeur, Jan; Vermeulen, Nico; Ehlers, Andreas; Lammertsma, Koop; Gooijer, Cees; Zwan, Gert // Journal of Biological Inorganic Chemistry;Jul2007, Vol. 12 Issue 5, p645 

    Cytochrome P450 2D6 (CYP2D6) is one of the most important cytochromes P450 in humans. Resonance Raman data from the T309V mutant of CYP2D6 show that the substitution of the conserved I-helix threonine situated in the enzyme’s active site perturbs the heme spin equilibrium in favor of the...

  • Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Hicks, J K; Swen, J J; Thorn, C F; Sangkuhl, K; Kharasch, E D; Ellingrod, V L; Skaar, T C; Müller, D J; Gaedigk, A; Stingl, J C // Clinical Pharmacology & Therapeutics;May2013, Vol. 93 Issue 5, p402 

    Polymorphisms in CYP2D6 and CYP2C19 affect the efficacy and safety of tricyclics, with some drugs being affected by CYP2D6 only, and others by both polymorphic enzymes. Amitriptyline, clomipramine, doxepin, imipramine, and trimipramine are demethylated by CYP2C19 to pharmacologically active...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics