| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 12, December 2006
Contents
Novel Targets for Anti-Viral Treatments
Guest Editor: Sabine C. Piller
Editorial Pp. 1561
Mucosal Transmission of HIV-1: First Stop Dendritic
Cells Pp. 1563-1569
J. Wilkinson and A.L. Cunningham
[Abstract]
The IL-7/IL-7 Receptor Axis: Understanding its
Central Role in T-Cell Homeostasis and the Challenges Facing
its Utilization as a Novel Therapy Pp. 1571-1582
S.C. Sasson, J.J. Zaunders and A.D. Kelleher
[Abstract]
Cellular Interactions of Virion Infectivity Factor
(Vif) as Potential Therapeutic Targets: APOBEC3G and More?
Pp. 1583-1593
J.M. Carr, A.J. Davis, F. Feng, C.J. Burrell and P. Li
[Abstract]
Will Diverse Tat Interactions Lead to Novel Antiretroviral
Drug Targets? Pp. 1595-1606
D. Harrich, N. McMillan, L. Munoz, A. Apolloni and L.
Meredith
[Abstract]
RNA as A Target for Host Defense and Anti-HIV Drugs
Pp. 1607-1613
G.C. Fanning
[Abstract]
Lipid Membrane; A Novel Target for Viral and Bacterial
Pathogens Pp. 1615-1621
D.J. Hawkes and J. Mak
[Abstract]
Dengue Virus RNA Polymerase NS5: A Potential Therapeutic
Target ? Pp. 1623-1638
S.M. Rawlinson, M.J. Pryor, P.J. Wright and D.A. Jans
[Abstract]
Pharmacogenetic and Pharmacogenomics
Guest Editors: A. LLerena and J. Licinio
Editorial Pp. 1639-1640
Ethnic Differences in Pharmacogenetically Relevant
Genes Pp. 1641-1648
R.M. Engen, S. Marsh, D.J. Van Booven and H.L. McLeod
[Abstract]
Pharmacogenomics in the Americas: The Impact of Genetic
Admixture Pp. 1649-1658
G. Suarez-Kurtz and S.D.J. Pena
[Abstract]
Serotonin Transporter Gene Variants and Behavior:
A Comprehensive Review Pp. 1659-1669
A. Serretti, R. Calati, L. Mandelli and D. De Ronchi
[Abstract]
Clinical Implications of CYP2D6 Genetic Polymorphism
During Treatment with Antipsychotic Drugs Pp. 1671-1680
P. Dorado, R. Berecz, E.M. Peñas-LLedó,
M.C. Cáceres and A. LLerena
[Abstract]
Susceptibility Genes for the Side Effect of Antipsychotics
on Body Weight and Obesity Pp. 1681-1695
Y.C. Chagnon
[Abstract]
The Pharmacogenetics of Asthma Therapy Pp.
1697-1708
K.G. Tantisira and S.T. Weiss
[Abstract]
Pharmacogenetics of Cytochromes P450 in Tropical Medicine
Pp. 1709-1719
V. Ribeiro and I. Cavaco
[Abstract]
Why should We Bother? Ethical and Social Issues in
Individualized Medicine Pp. 1721-1727
N.W. Paul and H. Fangera
[Abstract]
Abstracts
[Back
to top]
Editorial
This special edition of Current Drug Targets entitled
“Novel targets for anti-viral treatments” was
inspired by the recent advances in the HIV field. Despite
intense research over more than two decades there are still
several unresolved questions regarding the detailed molecular
mechanism of several of the HIV proteins, their interaction
with cellular proteins and the effect of such interactions.
With the emergence of drug resistant and recombinant HIV strains,
a renewed interest in elucidating basic molecular mechanisms
of viral protein interactions with the host cells was sparked.
The difficulties encountered with the development of a successful
vaccine further encouraged basic research into a better understanding
of the viral-host interactions in the hope of identifying
novel drug targets. Recent advances in technology including
the development of siRNA technology, microarray technology
and increased use of advanced laser scanning confocal microscopy
techniques to visualize fluorescently labelled proteins have
all substantially contributed to a better understanding of
many viral replication steps and hence the identification
of novel drug targets, some of which may be relevant to viruses
other than HIV.
In this edition seven examples of the latest exciting advances
of exploring novel antiviral drug targets are covered. Firstly,
insights into the biology of dendritic cells and their unique
role for virus dissemination to the draining lymph nodes are
discussed. Development of microbicides that are capable of
preventing transmission of virus at mucosal sites particularly
during sexual transmission of HIV, which is greatly on the
increase in developing countries, will need to include protection
of dendritic cells. The discovery of C-type lectin receptors
and their unique distribution on various subsets of dendritic
cells may prove an exciting new target for the development
of microbicides and several novel strategies are discussed
by Wilkinson and Cunningham. This is followed by a discussion
on the potential use of IL-7 in HIV as wells as cancer treatment.
With IL-7 being currently used as adjuvant therapy in phase
I/II clinical trials, the review by Sasson et al.
highlights the importance of a detailed understanding of the
IL-7/IL-7 receptor system in order to develop safe new therapeutics
that are able to manipulate the signalling through this system
resulting in beneficial outcomes not only for HIV treatment
but in a number of lymphopenic conditions. Identifying cellular
interactions of viral proteins has vastly increased our understanding
of cellular processes and opened new potential targets for
antiviral therapy which is nicely exemplified by the contributions
of Carr et al. and Harrich et al. on the
interaction of the HIV protein Vif with the cellular protein
APOBEC3G and the interactions of the HIV protein Tat with
cellular proteins such as protein kinase R, p300/CBP, P/CAF,
cyclin T1, and RNA polymerase II, respectively. In addition,
both Vif and Tat also interact with other HIV proteins and
are involved in protease activity, virus packaging and reverse
transcription, respectively. A better understanding of these
and other steps of viral replication and the involvement of
each and every viral protein will be essential for the future
development of specifically targeted anti-HIV drugs. Another
potential drug target is the genetic material of HIV, RNA
itself or RNA intermediates as discussed in Fannings’
review which gives an exciting insight into the co-evolution
of cellular responses to signature viral RNA intermediates
and the counter measures employed by viruses. Fanning further
explores the potential use of the latest technologies such
as RNAi and siRNA in the treatment of HIV. Advances in the
lipid biology field with the discovery of specialised membrane
areas, the lipid rafts, which are cholesterol rich and non-ionic
detergent resistant, have also been taken into consideration
for potential drug development against a variety of pathogens
that rely on the presence of lipid rafts for their entry and
replication as reviewed by Hawkes and Mak. Reagents that can
interfere with lipid rafts may turn out to become a great
addition to topical microbicide development. Last but by no
means least, Rawlinson et al. review the biology
of the flavivirus that causes dengue fever and dengue hemorrhagic
fever which is the most common arthropod-borne viral infection.
In particular, one of its non-structural proteins, NS5 is
identified as an ideal drug target candidate due to its important
role in two essential processes of dengue replication.
These reviews are by no means the only areas of intense research
but are just some examples of the exciting field devoted to
discovering potential anti-viral targets. The articles in
this special issue have all highlighted the importance of
a better, more detailed understanding of each step of virus
replication at a molecular level in order to be able to develop
novel drugs in the combat of new and emerging viral diseases.
I am looking forward to the results of the next 20 years in
this exciting and expanding area of research.
Sabine C. Piller
Westmead Millennium Institute,
Darcy Road Westmead NSW 2145
Australia
E-mail: sabine_piller@wmi.usyd.edu.au
[Back to top]
Mucosal Transmission of HIV-1: First Stop Dendritic Cells
J. Wilkinson and A.L. Cunningham
Worldwide the heterosexual route is the prevalent mode
of transmission of HIV, increasing the demand for measures
that block the sexual spread of HIV infection. Vaccines designed
to prevent mucosal transmission of HIV should be considered
a component of vaccine strategies against HIV (in addition
to cytotoxic T cells required for clearance and to prevent
viral dissemination) and include antibodies, which are capable
of blocking HIV entry at mucosal epithelial barriers, and
prevent initial infection of target cells in the mucosa. However,
in the interim and in the absence of an effective vaccine,
the development of microbicides, topical preparations that
block the early steps of HIV infection and transmission, may
represent a more viable alternative to condom use in many
HIV infected regions of the world especially by empowering
women. To date there has been some success with antiviral
antibodies applied as a microbicide capable of preventing
SIV infection in macaques [1] and reports of vaccines capable
of preventing intravaginal and intrarectal inoculated SIV
[2 , 3]. However, for such success in humans a much greater
understanding of the mechanisms involved in the very early
stages of mucosal transmission in HIV infection are required.
These may lead to additional strategies to inactivate or inhibit
viral uptake and replication before a potentially life threatening
acute infection develops. Such measures will lead to the development
of effective microbicides and vaccines that will diminish
the global spread of HIV.
[Back to top]
The IL-7/IL-7 Receptor Axis: Understanding its
Central Role in T-Cell Homeostasis and the Challenges Facing
its Utilization as a Novel Therapy
S.C. Sasson, J.J. Zaunders and A.D. Kelleher
Interleukin-7 (IL-7) is a cytokine produced predominantly
by stromal cells of the thymus and bone marrow and is essential
for lymphopoiesis. This paper reviews the importance of IL-7
and its receptor (IL-7R) in T-cell genesis, peripheral survival,
expansion and memory T-cell development. IL-7 is of particular
importance in lymphopenic conditions. Its expression is up-regulated
in a number of lymphopenic conditions including: marrow ablation
prior to bone marrow transplantation, marrow suppression following
chemotherapy and human immuno-deficiency virus (HIV) infection.
Plasma IL-7 levels inversely correlate with CD4+ T-cell counts
in these conditions. Animal models suggest that IL-7 improves
immune reconstitution through increasing thymic output and,
perhaps more importantly, through antigen-independent homeostatic
driven proliferation in the periphery. Given the promising
preliminary data on the use of IL-7 adjuvant therapy in simian
immuno-deficiency virus (SIV) infected non-human primates,
IL-7 has recently moved into Phase I/II clinical trials of
its role as a possible adjuvant therapy for cancer and HIV
infection. This paper discusses important considerations such
as the possible negative impacts of IL-7 on increased viral
infectivity, the induction of autoimmunity and risk of neoplastic
events. Successful use of IL-7 will rely on further understanding
of the regulation of the component parts of the IL-7R system.
Ultimately this understanding may lead to therapeutics that
manipulate and optimise signalling through the IL-7/IL-7R
system.
[Back to top]
Cellular Interactions of Virion Infectivity Factor
(Vif) as Potential Therapeutic Targets: APOBEC3G and More?
J.M. Carr, A.J. Davis, F. Feng, C.J. Burrell and P. Li
Vif is an HIV accessory protein whose primary function is
to negate the action of APOBEC3G, a naturally occurring cellular
inhibitor of HIV replication. Vif acts by binding to APOBEC3G,
inducing its protein degradation within infected cells and
reducing its levels in progeny virions. Interventions that
interfere with the Vif-APOBEC3G interaction, raise intracellular
or virion associated levels of APOBEC3G, or reduce intracellular
levels of Vif, all could hold promise as potential therapeutic
approaches aimed at enhancing the cells innate antiviral activity.
Levels of APOBEC3G might be increased or Vif levels decreased,
by strategies targeting protein synthesis, protein degradation
or cellular localisation and function, and properties of APOBEC3G
and Vif relevant to these strategies are discussed. Recent
data have suggested that Vif may have other mechanisms of
action apart from the above activities against APOBEC3G, including
effects against other anti-viral mechanisms independent of
APOBEC3G cytidine deaminase activity. In addition to interaction
with APOBEC3G, Vif may have other accessory functions, which
are discussed in relation to potential therapies that may
affect multiple stages of the HIV life cycle. Future development
of strategies that combine enhancement of APBOEC3G functional
with inhibition of multiple Vif functions may become useful
tools for HIV therapy.
[Back to top]
Will Diverse Tat Interactions Lead to Novel Antiretroviral
Drug Targets?
D. Harrich, N. McMillan, L. Munoz, A. Apolloni and L.
Meredith
More than fifteen years following the description of Tat as
a critical HIV gene expression regulatory protein, additional
roles for Tat in HIV replication have been described, including
reverse transcription. Tat achieves function through direct
interaction with viral proteins, including reverse transcriptase,
and numerous cellular proteins including cyclin T1, RNA polymerase
II, protein kinase R (PKR), p300/CBP, and P/CAF. Despite our
advanced knowledge of how Tat operates, this has not yet resulted
in the discovery of effective agents capable of targeting
various Tat functions. Nevertheless, Tat remains an attractive,
virus-specific molecule and detailed understanding of specific
protein interaction holds promise for future drug discovery.
[Back to top]
RNA as A Target for Host Defense and Anti-HIV Drugs
G.C. Fanning
Viruses have many strategies for negotiating entry into cells
and harnessing the cellular machinery for their propagation
[1, 2]. The diversity of strategies is however bound by the
central process of translating protein from RNA. The co-evolution
of cellular responses to signature viral RNA intermediates
and the counter measures employed by viruses, highlight the
vulnerability of this aspect of viral replication and the
potential of viral RNA as a drug target. In this review we
will discuss novel efforts to target the RNA intermediates
of the HIV life cycle.
[Back to top]
Lipid Membrane; A Novel Target for Viral and Bacterial
Pathogens
D.J. Hawkes and J. Mak
Lipid rafts are defined as specialized, dynamic microdomains
that can be found in plasma membrane, and they are enriched
with cholesterol and sphingolipids. Since lipid rafts’
first debut in the mid 1990’s, their existence, function
and biological relevance have been a subject of intense scrutiny
within the scientific community. Throughout this debate, we
have learned a great deal regarding how cargos (both pathogens
and cellular factors) are transported into and out of the
cell through raft-dependent or raft-independent pathways.
It is now apparent that a number of toxins, bacterial-, and
viral-pathogens are able to exploit cholesterol and/or lipid
rafts to gain a foot hold in their target hosts. The objective
of this review is to describe our current appreciation on
how selected pathogens utilise cholesterol and/or lipid rafts
to support their propagation and to speculate on how some
of these observations can be explored for the development
of novel strategies that target plasma membrane lipids to
control the spread of these viral- and bacterial-pathogens.
[Back to top]
Dengue Virus RNA Polymerase NS5: A Potential Therapeutic
Target ?
S.M. Rawlinson, M.J. Pryor, P.J. Wright and D.A. Jans
Dengue fever (DF)/dengue haemorrhagic fever (DHF) is the most
common arthropod-borne viral infection, where it is now estimated
that 2.5-3 billion people world-wide are at risk of infection.
Currently there is no available treatment, in the form of
vaccine or drug, making eradication of the mosquito vector
the only viable control measure, which has proved costly and
of limited success. There are a number of different vaccines
undergoing testing, but whilst a dengue vaccine is clearly
desirable, there are several issues which make live-attenuated
vaccines problematic. These include the phenomenon of antibody-dependent
enhancement (ADE) and the possibility of recombination of
attenuated vaccine strains with wild-type flavivirus members
reverting vaccines to a virulent form. Until we gain a better
understanding of these issues and their associated risks,
the safety of any live dengue vaccine cannot be assured. It
therefore may be safer and more feasible for therapeutic-based
approaches to be developed as an alternative to live vaccines.
As our understanding of dengue molecular biology expands,
new potential targets for drugs are emerging. One of the most
promising is the dengue non-structural protein 5 (NS5), the
largest and most highly conserved of the dengue proteins.
This review examines the unique properties of NS5, including
its functions, interactions, subcellular localisation and
regulation, and looks at ways in which some of these may be
exploited in our quest for effective drugs.
[Back to top]
Editorial
The Clinical Relevance of Pharmacogenetics in the Twenty-First
Century
A major cause of morbidity and mortality in contemporary medicine
is the outcome of interindividual differences in therapeutic
response, drug interactions, and adverse drug reactions. The
scope of the problem will only increase because the population
ages and grows fatter, the rates of chronic illness rise and
the use of multiple medications for extended periods becomes
increasingly more common. Negative outcomes to pharmacologic
treatment are partly related to genetic and environmental
factors influencing pharmacokinetic and pharmacodynamic phases.
Interindividual differences in plasma concentrations in patients
treated with the same doses if the same drugs have been demonstrated.
Variability might also be at the level of receptors, transporters,
etc. Despite the growing body of experimental and pharmacological
research results, the clinical consequences of genetically
inherited differences in drug metabolism are poorly established.
Meanwhile, knowledge of pharmacogenetics of receptors and
other pharmacodynamic targets is also increasing.
The sources of variability in the elimination of a drug are
genetic (polymorphisms) and environmental (food intake, drug
interactions, etc.). Additionally, the potential influence
of physiological factors (gender, age, etc.) and the involvement
of homeostatic mechanisms, including endogenous metabolism,
must be taken into consideration.
Such variability can be manifested interindividually (between
individuals) or interethnically (between populations). The
evaluation of the relevance for patients of the specific factors
requires well-defined clinical studies.
The use of phenotyping and genotyping and measurements of
drugs and drug metabolites with simultaneous evaluation of
response and side effects in prospective studies may give
clues to the clinical significance of these effects. Nevertheless,
physicians today need to be aware of pharmacogenetic factors,
which could influence drug therapy, and should take into account
this possibility as a potential cause of undesired effects
or therapeutic failure [1].
It would be highly desirable that when a new drug is marketed
the knowledge of interindividual and interethnic differences
in drug response due to pharmacogenetic factors should be
known and considered in order to optimize treatment and improve
the cost/benefit ratio [2].
There is a growing consensus on the potential use of pharmacogenetics
in clinical practice, and hopes have been expressed for their
potential in the development of global health. However, there
are two major concerns that may lead to widening the “biotechnological
gap” between the developing and the industrialized world:
first the unaffordability of some current biotechnological
methods for poorer countries, and second the unpredictability
of categorizing patients by ethnicity (which is a construct
with a substantial social substrate) makes it necessary to
analyze multiple described alleles for individual clinical
cases. As of today, conventional PCR methodology is available,
and automatization using chips is a reality. However, in the
near future the development of a variety of methods may decrease
the direct cost, so that it will be easier to implement pharmacogenetic
analyses as a routine in the clinic [3].
The sequencing and haplotype mapping of the human genome
have in the context of increasingly admixtured populations
made it feasible and desirable to genotype the most frequent
known functional alleles in a given clinical situation [3].
For example, CYP2C9 and CYP2D6 allele frequencies
vary between populations and geographical areas, so that in
admixtured populations (e.g., in North, Central, and South
America) it would be very useful to have genotyping methods
that would allow the phenotype of a given patient or healthy
volunteer to be predicted. In the present Hot-Topic Issue,
two papers deal with this problem (“Ethnic
Differences in Pharmacogenetically Relevant Genes”,
by R M Engen et al., and ”Pharmacogenomics
in the Americas: The Impact of Genetic Admixture”
by G. Suarez-Kurtz and S. D. J. Pena). An individualized pharmacogenetic
approach would allow recommended dosages to be adjusted for
each location, considering the growing body of knowledge emerging
from pharmacogenetics.
Another important aspect to consider as a source of variability
is the potential involvement of pharmacogenetic mechanisms
in endogenous functioning. Several decades ago, the potential
involvement was described of varying allele frequency of one
of the most relevant drug metabolizing enzymes, CYP2D6, in
psychological factors [4,5]. Since then, although several
works have addressed the topic, it remains unclear. In the
present issue A. Serretti et al. add another view
with potential links to pharmacodynamics in their review “Serotonin
transporter gene variants and behaviour”.
There have been calls for the use of biotechnologies and pharmacogenetics
for global health by improving the drug-treatment of the most
important diseases. We cover here the use of pharmacogenetics
in relevant clinical problems: psychiatric disorders, by Dorado
et al. (“CYP2D6: clinical use during treatment
with antipsychotic drugs”) and Chagon et al.
(“Susceptibility genes for the side effect of antipsychotics
on body weight and obesity”), respiratory diseases by
Tantisira et al. (“The pharmacogenetics of
asthma therapy”), and infectious diseases by Marques
et al. (“Pharmacogenetics and tropical pharmacology”).
Considering the rapid growth of knowledge and relevance of
critically sensitive issues such as informed consent, and
the use and storage of DNA [6], we devoted the last review
by Paul et al. to “Ethical aspects of pharmacogenetics”.
We expect that the growing body of knowledge of pharmacogenetics
and the necessary development of affordable methodologies
that can lead to translation of this field into routine clinical
practice will result in the improvement of clinical care and
enhanced global health. Such new approaches might additionally
contribute to narrow the biotechnological gap between developed
and emerging countries.
References
[1] Kirchheiner, J.; Fuhr, U.; Brockmöller, J. (2005)
Nat. Rev. Drug Discov. 4, 639-647.
[2] Shah, R.R. (2005) Philos Trans. R. Soc. Lond. B. Biol.
Sci. 360(1460), 1617-1638.
[3] Dorado, P.; Cáceres, M.C.; Pozo-Guisado, E.; Wong,
M-L.; Licinio, J.; Llerena, A. (2005) Biotechniques
39(4), 571-574.
[4] Llerena, A.; Edman, G.; Cobaleda, J.; Benitez, J.; Schalling,
D.; Bertilsson, L. (1993) Acta Psychiatr. Scand.
87(1), 23-28.
[5] Llerena, A.; Cobaleda, J.; Benitez, J. (1989) Lancet
17,1(8651), 1398.
[6] Licinio, J.; Wong, M-L. (2002) Pharmacogenomics J.
2(6), 343-344.
Adrián LLerena MD
University of Extremadura Medical School,
Director CICAB. Clinical Research Centre,
Extremadura University Hospital,
Av de Elvas s/n, E-06071, Badajoz, Spain
Tel: and Fax: +34 924 289675
E-mail: allerena@unex.es
and CIS, University of Beira Interior,
Covilhã, Portugal
Julio Licinio, M.D.
Professor and Chairman
Department of Psychiatry & Behavioral Sciences (D-28)
University of Miami Miller School of Medicine
1695 NW 9th Avenue, Suite 3100
Miami, Florida 33136, USA
Tel: (305) 355-9105
Fax: (305) 355-9099 or (305) 355-9103
E-mail: licinio@miami.edu
[Back to top]
Ethnic Differences in Pharmacogenetically Relevant
Genes
R.M. Engen, S. Marsh, D.J. Van Booven and H.L. McLeod
There is great heterogeneity in the way humans respond to
medications, often requiring empirical strategies to define
the appropriate drug therapy for each patient. Genetic polymorphisms
in drug metabolizing enzymes, transporters, receptors, and
other drug targets provide putative markers for predicting
which patients will experience extreme toxicity and treatment
failure. Both quantitative (allele frequency) and qualitative
(specific allele) differences for polymorphic genes have been
observed between different population groups. For example,
the frequency of mutations in thiopurine methyltransferase
is lower in Chinese than Caucasian populations. In addition,
the predominant mutation responsible for deficient enzyme
activity differs between the two populations (TPMT*3C versus
TPMT*3A). Understanding the influence of ethnicity on pharmacogenomics
will allow for comprehensive strategies for using the genome
to optimize therapy for patients throughout the world.
[Back to top]
Pharmacogenomics in the Americas: The Impact of Genetic
Admixture
G. Suarez-Kurtz and S.D.J. Pena
In this review we focus on the impact of genetic admixture
on pharmacogenomics in the American continent, where five
centuries of intermarriage between Amerindians, European and
Africans, resulted in the extensive population heterogeneity
observed nowadays. We compare two alternative views of human
genomic variation, one stressing populations and the other
stressing individuals, and discuss their important and far-reaching
consequences to implementation of pharmacogenetics/genomics
in practice, especially when dealing with admixed populations.
We conclude that a variable mosaic genome paradigm, which
envisages the genome of any particular individual as a unique
mosaic of variable haplotype blocks - has considerably higher
explanation and predictive power for the populations of the
Americas. We then move to the more formal pharmacogenomics
arena to examine the pharmacogenetic/pharmacogenomic diversity
in the Americas and review the challenges and advantages of
admixed populations for pharmacogenomic studies. Because interethnic
admixture is either common or increasing at a fast pace in
many, if not most populations, extrapolation on a global scale
of pharmacogenomic data from well-defined ethnic groups is
plagued with uncertainty. Intraethnic diversity adds complexity
to the scientific appraisal, regulatory decisions and, eventually,
prescribing of drugs purportedly targeted to a given “race”
or ethnicity. Pharmacogenetics/genomics has the potential
to benefit people worldwide and to reduce the health disparities
between developing and developed nations. This goal is unlikely
to be achieved by relinquishing the notion of personalized
drug therapy tailored to individual genetic characteristics
- the original promise of pharmacogenetics - in favor of a
model (pharmacogenomic?) of population-based drug development
and prescription, with all its potential pitfalls, especially
when extended to admixed populations in developing or developed
nations.
[Back to top]
Serotonin Transporter Gene Variants and Behavior:
A Comprehensive Review
A. Serretti, R. Calati, L. Mandelli and D. De Ronchi
The serotonin system modulates affective, cognitive and behavioral
processes. A key molecular structure of this system, the serotonin
transporter (SERT) gene, has been associated with many human
behaviors, both normal and pathological. This article aim
is a comprehensive overview of the human behavioral features
influenced by SERT gene variants and to suggest some comprehensive
hypotheses.
In particular, the SERTPR insertion/deletion polymorphism
has been related to hippocampal volume and amygdala response
and it has been found to influence anxiety-related personality
traits and anxiety disorders; in mood disorders it showed
some influences on age at onset, periodicity, illness recurrence,
rapid cycling, antidepressants response and depressive reaction
to stressful life events. Psychosomatic disorders, suicide,
alcoholism, smoking, eating disorders, attention deficit hyperactivity
disorders and autism have been also found to be related to
SERTPR variants.
SERT gene variants seem therefore to modulate a wide range
of aspects in both normal and affected individuals, many of
which are possibly due to indirect correlations between such
human features.
[Back to top]
Clinical Implications of CYP2D6 Genetic Polymorphism
During Treatment with Antipsychotic Drugs
P. Dorado, R. Berecz, E.M. Peñas-LLedó,
M.C. Cáceres and A. LLerena
CYP2D6 is described as the most relevant enzyme in the metabolism
of many antipsychotic drugs. Its contribution to the interindividual
differences in drug response is reviewed here highlighting
its role in the kinetics of antipsychotic drugs and the occurrence
of drug interactions.
The activity of CYP2D6 is inherited as a monogenetic trait
and the CYP2D6 gene appears highly polymorphic in
humans. The polymorphic alleles may lead to altered activity
of the CYP enzymes causing absent, decreased (poor), or increased
(ultrarapid) metabolism that in turn influence the disposition
of the antipsychotic drugs. Antipsychotic drug biotransformation
is mainly determined by genetic factors mediating CYP2D6
gene polymorphism, however the importance of environmental
factors (dietary, smoking, diseases, etc.) is also recognized.
Additionally, the potential interaction between CYP2D6
and the endogenous metabolism must be taken into consideration.
The present review summarizes the relevance of physiological
and environmental factors in CYP2D6 hydroxylation capacity,
the inhibition of CYP2D6 activity during treatment, the use
of drug/metabolite ratio as a tool to evaluate CYP2D6 hydroxylation
capacity in a patient, and the relevance of CYP2D6 for drug
plasma concentration and for QTc interval lengthening during
treatment with antipsychotic drugs.
[Back to top]
Susceptibility Genes for the Side Effect of Antipsychotics
on Body Weight and Obesity
Y.C. Chagnon
Antipsychotic-induced body weight gain is becoming a major
health concern since the increasing use of this medication
in different mental disorders with a high prevalence in different
populations. The percentage of patients gaining weight following
antipsychotic medication can reach up to 80% according to
the antipsychotic used, with around 30% developing obesity.
The origins of this adverse effect of antipsychotics are probably
multifactorial with the environment (food and exercise habits,
medication) and the genetics coming into play. We have compiled
the available genetic results on the antipsychotic-induced
body weight gain and obesity. Candidate genes analysis showed
that six genes have been associated with this adverse effect
of antipsychotics. Among these, the associations with the
serotonin receptor 2C and the leptin genes have been observed
in more then one study. Thirteen other genes, mainly antipsychotic
known receptors, have shown negative results. To find informative
gene variations, we have also compared the effects of some
polymorphisms of the serotonin receptor 2C and 2A in mental
disorders, for antipsychotic therapeutic effect, for antipsychotic
neuronal side effects, and for obesity. We have found results
for six polymorphisms in each of the two genes. When association
was observed for more then one phenotype, the same genotype
or allele was generally involved identifying those sensitive
to environmental pressures and to genetic background. Animal
transgenic models of knockout or overexpressed genes of antipsychotic
receptors have been evaluated for changes in obesity-related
phenotypes. Seventeen out of the twenty-three antipsychotic
receptors with transgenic models showed some effects on obesity-related
phenotypes. Ten of these receptors have not been tested yet
for antipsychotic-induced body weight gain, while the others
have been tested only once with negative results, or is already
associated to the effect such as the serotonin receptor 2C.
Finally, pharmacogenomic approaches have allowed to detect
more then 300 possible candidate genes for antipsychotic-induced
body weight gain.
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The Pharmacogenetics of Asthma Therapy
K.G. Tantisira and S.T. Weiss
Asthma affects an estimated 300 million individuals worldwide,
resulting in substantial morbidity, mortality, and health
care utilization. The response to the three major classes
of asthma therapy, β-agonists,
leukotriene antagonists, and inhaled corticosteroids, demonstrates
wide inter-individual variability, with a significant number
of non-responders. In addition, both asthma itself and the
intermediate phenotypes of asthma that are measured in response
to therapy, including the forced expiratory volume at one
second (FEV1), are highly heritable. Both of these
facts indicate that a significant portion of the therapeutic
response to asthma may be determined by genetic factors. This
review summarizes the asthma pharmacogenetics literature as
it pertains to human studies, focusing on asthma pharmacogenetic
phenotypes and human genetic association studies that have
been published for response to each of the three major classes
of asthma therapy. Of the four major classes of pharmacogenetic
response, there is now evidence that genetic factors influencing
the pharmacokinetics, the pharmacodynamics, and the disease
modification of asthma therapies may form the basis of credible
pharmacogenetic associations. Altogether, the available data
indicate that an individual’s likelihood of responding
to a given therapy is influenced by genetics. Therefore, genetic
testing may play a significant role in the care for individuals
with asthma in the forseeable future.
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Pharmacogenetics of Cytochromes P450 in Tropical Medicine
V. Ribeiro and I. Cavaco
Drug response is affected by genetic and non-genetic factors,
such as dietary compounds, sex, disease status and multiple
drug therapy. Inherited determinants of drug disposition remain,
however, the major cause of inter-individual differences due
to pharmacogenetic polymorphism in drug metabolizing enzymes
and transporters, or drug targets.
Differences on ethnicity may have a profound impact on drug
clearance, affecting the safety, efficacy and dosing regimen.
In the context of tropical regions, the situation may be even
more serious due to endemic infectious diseases and multiple
drug therapy, which may affect drug clearance.
In this review, we focus on the pharmacogenetics of the Cytochrome
P450 superfamily, responsible for the highest contribution
for variability among drug metabolizing enzymes, among ethnic
groups from tropical settings.
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Why should We Bother? Ethical and Social Issues in
Individualized Medicine
N.W. Paul and H. Fangera
Individualized medicine, methodologically rooted in pharmacogenetics
and pharmacogenomics, is now venturing into clinical application.
Prescribing the right drug in the right dose to the right
patient according to specific health needs and individual
characteristics is a core mission of individualized medicine.
The intrinsic values of this mission are so self-evident that
– at first glance – the ethical and social issues
raised by individualized medicine seem to be negligible. However,
the translation of pharmacogenetics and pharmacogenomics into
clinical routine not only requires the collection and evaluation
of large amounts of individual genetic data, but also heralds
the need for further clinical studies on the applicability
of genotype-related pharmacotherapy. Both requirements raise
a set of specific normative issues.
We argue that ethical and social questions of the desirability
and applicability of individualized medicine should be integrated
in a reconstructive approach to biomedical ethics, which is
guided by criteria of social accountability. As a first step,
we analyse the ethical and social issues of individualized
medicine in the transition to clinical practice, using social
accountability heuristically and as an evolutionary approach.
Since the pharmacogenetics and pharmacogenomics of neuropsychiatric
disorders are among the most advanced fields of individualized
medicine, as a second step we use depressive disorders to
elucidate the specific, crucial ethical and social questions
involved in assessing patients’ situations, disease
entities and phenotypes to relate them to genetic variations
for the purpose of individualized drug regimens.
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