Genetic Variability of Drug-Metabolizing Enzymes: the Dual Impact on Psychiatric Therapy and Regulation of Brain Function
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Molecular Psychiatry (2013) 18, 273 -- 287 & 2013 Macmillan Publishers Limited All rights reserved 1359-4184/13 www.nature.com/mp EXPERT REVIEW Genetic variability of drug-metabolizing enzymes: the dual impact on psychiatric therapy and regulation of brain function JC Stingl1,4, J Brockmo¨ ller2 and R Viviani3 Polymorphic drug-metabolizing enzymes (DMEs) are responsible for the metabolism of the majority of psychotropic drugs. By explaining a large portion of variability in individual drug metabolism, pharmacogenetics offers a diagnostic tool in the burgeoning era of personalized medicine. This review updates existing evidence on the influence of pharmacogenetic variants on drug exposure and discusses the rationale for genetic testing in the clinical context. Dose adjustments based on pharmacogenetic knowledge are the first step to translate pharmacogenetics into clinical practice. However, also clinical factors, such as the consequences on toxicity and therapeutic failure, must be considered to provide clinical recommendations and assess the cost-effectiveness of pharmacogenetic treatment strategies. DME polymorphisms are relevant not only for clinical pharmacology and practice but also for research in psychiatry and neuroscience. Several DMEs, above all the cytochrome P (CYP) enzymes, are expressed in the brain, where they may contribute to the local biochemical homeostasis. Of particular interest is the possibility of DMEs playing a physiological role through their action on endogenous substrates, which may underlie the reported associations between genetic polymorphisms and cognitive function, personality and vulnerability to mental disorders. Neuroimaging studies have recently presented evidence of an effect of the CYP2D6 polymorphism on basic brain function. This review summarizes evidence on the effect of DME polymorphisms on brain function that adds to the well- known effects of DME polymorphisms on pharmacokinetics in explaining the range of phenotypes that are relevant to psychiatric practice. Molecular Psychiatry (2013) 18, 273--287; doi:10.1038/mp.2012.42; published online 8 May 2012 Keywords: CYP2D6; CYP2C19; DME endogenous substrates; DME in brain; polymorphic DMEs; psychotropic drugs; pharmacogenetic dose adjustments INTRODUCTION pharmacogenetic testing in psychiatry and highlight clinical Many drug-metabolizing enzymes (DMEs) are affected by genetic situations in which it may be useful. polymorphisms resulting in variations in functional activity.1 Much less is known about the emerging picture of the function These genetic polymorphisms have been subjected to intense of these enzymes in the central nervous system when locally study, as they may be responsible for more than 10-fold expressed. In the second part of this review, we will review differences in drug clearance affecting therapy outcome and evidence suggesting that through their activity in the CNS, DMEs safety.2--5 Gradually, it also became clear that several DMEs are may affect therapy outcome and psychic processes independently expressed throughout the body, including the brain,6 suggesting from their action in the liver. Metabolism of drugs may take place that they may have a role in the regulation of physiological directly in brain tissue, but even more intriguingly, some evidence homeostasis by biotransformation of endogenous compounds.7 suggests that DMEs may be associated with psychological traits of Very different amounts of knowledge have been obtained on clinical significance. The aim of this review is to summarize the the role of DMEs in response to drugs, in vulnerability to the current state of knowledge on both aspects of DME function while effects of other xenobiotics, and in differences in biological considering the implications of their manifold roles. function through the action on endogenous ligands. For what concerns the pharmacogenetics of drug exposure, the impact of DME polymorphisms has been explored in hundreds of studies. PHARMACOGENETIC TESTING IN PSYCHOTROPIC DRUG THERAPY The maturity of the field is reflected by current discussions about Genetic variability of DMEs can affect all phases of drug the possibility of delivering ‘personalized medicine’ by making metabolism (Table 1). In phase I, lipophilic drugs or xenobiotics use of computerized databases to assess the cumulative empirical are transformed by oxidation reactions, reductions or hydrolysis to evidence and rationally justify pharmacogenetic dose adjust- more soluble compounds. Generally, this transformation corres- ments.8,9 In the first part of this review, we will summarize the ponds to detoxification and inactivation and facilitates hepatic or recent data on the influence of DME polymorphisms on renal excretion. However, xenobiotics may at times be activated to psychotropic drug therapy. We will also discuss strengths and toxic or therapeutically active compounds.10 Cytochrome P450 limitations of current assessments of the clinical utility of (CYP450) enzymes are the major family of enzymes mediating the 1Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany; 2Department of Clinical Pharmacology, University Medical Center, Georg-August-University, Go¨ ttingen, Germany and 3Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany. Correspondence: Professor JC Stingl, Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Kurt-Georg-Kiesinger-Allee 3, 53175 Bonn, Germany. E-mails: [email protected] and [email protected] 4Current address: Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany. Received 15 August 2011; revised 28 March 2012; accepted 3 April 2012; published online 8 May 2012 DME polymorphism in research and practice JC Stingl et al 274 Table 1. Polymorphic drug-metabolizing enzymes (DMEs) in psychiatry DME Phase of liver metabolism Main role Degree of polymorphism References CYP2D6 I Xenobiotics High 20,166 CYP2C19 I Xenobiotics High 159 CYP1A2 I Endobiotics Medium 167 CYP2C9 I Xenobiotics Medium 39 CYP3A4 I Xenobiotics Low 168 CYP2B6 I Endobiotics Medium 169 CYP2A6 I Endobiotics High 170 CYP2C8 I Xenobiotics Medium 56 CYP2E1 I Endobiotics Low 69 UGT1A4 II Xenobiotics Medium 171 UGT1A6 II Endobiotics Medium 171 UGT2B7 II Endobiotics Medium 171 UGT1A9 II Endobiotics Medium 171 Degree of polymorphism; high, alleles leading to complete enzyme deficiency; medium, polymorphic but still residual enzyme activity; low, rare genetic variants but no polymorphic phenotype.18,20 Liver CYP450 expression Brain CYP450 expression CYP1A2 CYP1B1 10% 8.0% CYP2D6 CYP3A4/5/7 CYP2C8/9/19 non-DME DME 6.0% non-DME DME CYP2J2 23% 15% 57.6% 42.4% 23% 77% 20.0% CYP2E1 7.5% CYP2E1 5% CYP1A1 0.2% CYP2D6 CYP2B6 CYP2A6 2% CYP3A5 0.2% CYP2B6 0.2% 1% 3% CYP2C8 0.3% Figure 1. The relative amount of expression of the CYP450 enzymes in the liver and brain is shown (data from Shimada et al.245 and Dutheil et al.66). One can see that the expression patterns in the brain and liver differ; the only enzymes that are expressed in substantial amounts in both organs are CYP2D6 and CYP2E1. Furthermore, the relative amount of CYP450 enzymes with DME activity varies, being higher in the liver. Furthermore, most of the CYP450 DMEs expressed in the brain possess DME activity only on individual compounds52 and are presumably primarily involved with endogenous substrates. CYP1B1, for example, metabolizes estradiol246 and CYP2J2 metabolizes ebastine and astemizole.247,248 phase I of drug metabolism.11 In the liver, most expressed CYP450 Proportion of psychotropic medications metabolized enzymes are involved in xenobiotic metabolism; in the brain, by individual enzymes however, they may be involved in endobiotic metabolism (that is biosynthesis or deactivation of endogenous compounds) (Figure 1). Locally expressed CYP450 enzymes or local endogenous substrates CYP3A4 may also modulate pharmacodynamics in the brain.12,13 In phase II, solubility of drugs is increased by conjugation CYP2D6 CYP2C19 with hydrophilic residues. The main DMEs involved in phase II metabolism are glucuronyl transferases (UGTs), N-acetyltrans- ferases, sulfonyltransferases and glutathione S-transferases. Phase CYP2C9 CYP2B6 CYP1A2 II DMEs present polymorphisms of varying functional significance. However, because most psychiatric drugs are extensively meta- bolized by phase I DMEs, the majority of pharmacogenetic effects of clinical significance are attributable to phase I, with a few notable exceptions like lamotrigine or morphine (Table 1, Figure 2). Among the phase I DMEs, CYP2D6 is particularly notable because Aldehyde Dopa- it is involved in the metabolism of approximately half of the oxidase decarboxylase COMT UGT1A4 commonly prescribed psychotropic drugs.14 Before and after biotransformation, most drugs are excreted or Figure 2. Relative contribution of individual DMEs in the metabolism taken up by transporters (often referred to as phase 0 or phase III of of psychopharmacological drugs estimated from involvement in the main metabolic pathways (based on data from Hiemke et al163). drug metabolism). Functional polymorphisms in drug transporters 15--17 As can be seen in the figure, the most important liver enzymes arebeyondthescopeofthisarticleandarereviewedelsewhere. involved in antidepressant and antipsychotic drug metabolism are DME phenotypes express wide ranges of clinically significant the CYP450 enzymes CYP2D6, CYP3A4, CYP2C19 and CYP1A2, and 18 variation and appear as almost monogenetic