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Current Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 4, Number 1, March 2006
Contents
Transposable Elements and their Use for Target
Site Specific Gene Delivery Pp. 1-8
A. Buzdin
[Abstract]
Pharmacogenomics of Xenobiotic Metabolizing Enzymes
in South American Populations Pp. 9-18
M.B. Filho, R.M. Albano, A. Rossini and L.F.R. Pinto
[Abstract]
Genetic and Pharmacogenetic Aspects of Alcohol-Dependence
Pp. 19-32
N. Ramoz, G. Schumann and P. Gorwood
[Abstract]
Defining Peptide Sequences: From Antigenicity to Immunogenicity
Through Redundancy Pp. 33-37
D. Kanduc
[Abstract]
Cancer Pharmacogenetics: The Move from Pharmacokinetics to
Pharmacodynamics Pp. 39-46
J.M. Hoskins and H.L. McLeod
[Abstract]
Relevance of Cytochrome P450 Polymorphisms in the
Treatment of Helicobacter pylori Infection and Gastroesophageal
Reflux Disease Pp. 47-56
C. Kirsch, A. Morgner and S. Miehlke
[Abstract]
Pharmacogenetics of Colon Cancer and Potential Implications
for 5-Fluorouracil-Based Chemotherapy Pp. 57-67
R. Mauritz and G.J. Peters
[Abstract]
Pharmacogenetics in Type 2 Diabetes: Polymorphisms
in Candidate Genes Affecting Responses to Antidiabetic Oral
Treatment Pp. 69-78
G. Sesti and M.L. Hribal
[Abstract]
Abstracts
[Back to top]
Transposable Elements and their Use for Target Site
Specific Gene Delivery
A. Buzdin
Transposable elements (TEs), which occupy nearly 40% of eukaryotic
DNA, are selfish repetitive sequences, able to proliferate
in the host genomes via either their DNA copies or
RNA intermediates utilizing the mechanism termed ‘reverse
transcription’ and the RNA-dependant DNA polymerase
enzyme, called reverse transcriptase. The newly formed DNA
copy of the element then integrates into the genome, using
a combination of host and self-encoded proteins, depending
on the transposable element origin. Being important model
objects for the study of many fundamental molecular biology
processes and by actively participating in the gene regulation
network, TEs are of great interest for basic researches in
molecular genetics and genomics. Their practical use, however,
is limited now to some fields of forensic sciences, phylogenetic
studies and population genetics. In this mini-review I have
tried to put together both theoretical, experimental and speculative
data on the use of the transposable elements as tools for
the gene delivery into the host eukaryotic genomes, producing
stable transgene transformants. The strength of the TE-based
constructions as compared with popular viral vectors would
be the predictable, genomic target sequence-specific transgene
integration, mediated by the enzymatic machinery of some TEs.
These and other implications of transposable elements in biomedical
sciences will be discussed.
[Back to top]
Pharmacogenomics of Xenobiotic Metabolizing Enzymes
in South American Populations
M.B. Filho, R.M. Albano, A. Rossini and L.F.R. Pinto
The toxicity that can result from the exposure to numerous
xenobiotics can vary greatly for each individual. This is
mainly due to differences in the activity of xenobiotic metabolizing
enzymes (XME) that participate in the disposal of toxic xenobiotics
from the human body. The genes that encode XMEs present a
variety of polymorphisms that occur in the promoter or coding
regions, resulting in differences in the amount or in the
catalytic activities of the enzymes. Human populations differ
regarding the frequency of alleles and haplotypes that are
present in a given geographic region. Genetic background and
ancestry are the main reasons for such variability. South
America, due to an extensive colonization period, is populated
by descendents of Amerindians, Africans and Europeans. The
admixtures that happened in each country, however, vary according
to historical and geographical conditions. Brazil, for example,
has one of the world's most admixed populations with genetic
contributions from several tribes of Amerindians, many still
existent, from Africans, and from various waves of European
immigrants. In this review we will discuss the frequency of
genetic polymorphisms of XMEs, particularly Cytochrome P450s
and Glutathione S-transferases, found in different populations
of South American countries. The genetic background and degree
of population admixture of each country is taken under consideration
in a discussion of the difficulties generated by enzyme polymorphisms
in the treatment of individuals within such populations.
[Back to top]
Genetic and Pharmacogenetic Aspects of Alcohol-Dependence
N. Ramoz, G. Schumann and P. Gorwood
Alcohol dependence is a frequent and complex disorder involving
both genetic (h2≈0.5) and environmental factors.
The definition of what is inherited with alcohol dependence
is still unknown. Shared liability has been detected with
other addictive disorders (mainly nicotine dependence), and
certain psychiatric disorders (such as bipolar disorder) and/or
personality disorders (specifically antisocial personality).
Such a broad spectrum may also explain the development of
antidepressants, mood regulators and/or anti-impulsive drugs
in the treatment of alcohol dependence. Genome wide scans,
analyses of alcohol metabolism and reward circuits have identified
many candidate genes or locations. Some genes linked to the
reward pathway of alcohol, may have pharmacogenetic relevancy,
such as the GABRA6 gene (regarding the role of benzodiazepine
in alcohol withdrawal), SLC6A4 gene (as serotonin
reuptake inhibitors may reduce alcohol intake in subgroups
of patients), CB1 gene (because the CB1
agonists modify alcohol consumption, at least in rodents),
and the OPRM1 gene (the 118G allele being associated
with increased chances of Naltrexone efficacy).
High-throughput approach for genotyping of polymorphisms,
transcriptomics, and proteomics are useful tools that will
help to identify susceptibility and protection genes for alcohol
diseases. Together, these tools could be used to develop a
rational pharmacogenomics strategy to test specific individual
treatment for alcohol dependence.
[Back to top]
Defining Peptide Sequences: From Antigenicity to Immunogenicity
Through Redundancy
D. Kanduc
The molecular biology era has allowed the exact definition
of the disease-associated–proteins (DAPs). The computational
era has analyzed full-length DAPs by antigenicity prediction
algorythms based on physico-chemical parameters. Today, proteomics
is providing a global comprehensive analysis of defined peptide
portions of DAPs. The fine profiling of the disease-associated
peptide repertoire is of particular importance in the definition
of qualities as antigenicity and immunogenicity, and is a
concrete promise of a bench-to-bedside translational research.
Identifying the peptide sequences within the DAPs, which may
potentially provoke (auto)immune responses, more than ever
emerges as the key strategy for effective immunotherapeutical
treatments in cancer diseases as well as infectious or autoimmune
pathologies. Here I draw a schematic picture of the experimental
attempts to define immunogenic peptide portions, describe
the principle of sequence uniqueness as a rationale for the
subproteomic analysis of DAPs and delineate the possible advantages
of a peptide-vaccine approach to the treatment of degenerative,
infectious and autoimmune diseases that might be effective
and devoid of collateral harmful effects.
[Back to top]
Cancer Pharmacogenetics: The Move from Pharmacokinetics
to Pharmacodynamics
J.M. Hoskins and H.L. McLeod
Drug response is a complex process determined by both genetic
and non-genetic factors. Factors that control drug response
can be divided into those that affect the systemic distribution
and the concentration of drug at its target (pharmacokinetics)
and those associated with drug targets and cellular downstream
effectors (pharmacodynamics). Most pharmacogenetic studies
to date have focused on the influence of genetic variation
in determinants of drug distribution. Consistent associations
between host polymorphisms in drug metabolising enzymes, including
UGT1A1, TPMT and DPD and patient toxicity or response to chemotherapies
have been demonstrated. Less is known about the cellular events
following exposure to anticancer agents that lead to DNA repair
or cell death, making them more difficult to study. Genetic
variation in these downstream effectors is a potential source
of interindividual differences in tumoral response. Exciting
associations between tumor sensitivity to tyrosine kinase
inhibitors and somatic mutations in their drug targets (for
example epidermal growth factor receptor (EGFR)) have recently
been demonstrated. These findings take us closer to personalized
therapy. This paper reviews the latest advances in cancer
pharmacogenetics with an emphasis on genetic variation in
drug targets and mediators of cellular events that occur following
drug-target interactions.
[Back to top]
Relevance of Cytochrome P450 Polymorphisms in the
Treatment of Helicobacter pylori Infection and Gastroesophageal
Reflux Disease
C. Kirsch, A. Morgner and S. Miehlke
Proton pump inhibitors (PPI) are widely used for the treatment
of gastroesophageal reflux disease (GERD), and in combination
with antibiotics for the treatment of Helicobacter pylori
infection. PPI are mainly metabolized by the polymorphic cytochromes
P450 2C19 and 3A4. Genetic polymorphisms of these genes with
resulting different enzyme activities may have an impact on
the clinical efficacy of PPI-based therapies.
There is increasing evidence that in Asian patient populations
the efficacy of PPI-based eradication therapies is influenced
by the patients CYP2C19 metabolizer status. Also two European
studies report on CYP2C19-dependent eradication rates of H.
pylori. In slow metabolizers, the AUC of oral PPI are
higher in comparison to extensive metabolizers resulting in
a stronger suppression of intragastric acid secretion. Recent
studies suggest that the healing rate of erosive GERD is also
influenced by the CYP2C19 metabolizer status. This review
focuses on the relationship between CYP2C19 polymorphisms
and clinical outcome after PPI based therapies in H. pylori
eradication and GERD.
[Back to top]
Pharmacogenetics of Colon Cancer and Potential Implications
for 5-Fluorouracil-Based Chemotherapy
R. Mauritz and G.J. Peters
The antimetabolite 5-fluorouracil (5-FU) is widely used
in combination treatment of patients with advanced stages
of colorectal cancer. In the last decade, several studies
focused on genetically determined variability in function
of certain enzymes that are involved in the metabolism of
5-fluoropyrimidines. Polymorphisms and mutations within the
thymidylate synthase (TS), methylenetetrahydrofolate reductase
(MTHFR) and dihydropyrimidine dehydrogenase (DPD) genes have
been associated with response to or toxicity from treatment
with 5-FU. Pharmacogenetic studies could therefore identify
genetic markers that can be used to guide the treatment for
each individual patient. However, the predictive role of these
genetic markers is not straightforward. Controversial data
have been found for polymorphisms in the TS gene. Similarly,
the role of MTHFR is not clear. Mutations in the DPD gene
seem more suitable to predict toxicity in part of the cases
but seems less suitable for prediction of response. These
inconsistencies across the literature regarding the impact
of identified TS, MTHFR and DPD polymorphisms on enzyme levels
and response to 5-FU-based drugs will be discussed in this
review. More comprehensive genetic evaluation by combined
analysis of several parameters is needed. To achieve this
novel approaches such as expression array and array-CGH offer
the best perspective.
[Back to top]
Pharmacogenetics in Type 2 Diabetes: Polymorphisms
in Candidate Genes Affecting Responses to Antidiabetic Oral
Treatment
G. Sesti and M.L. Hribal
Type 2 diabetes is a complex and heterogeneous metabolic
condition that has reached epidemic proportions, affecting
more than 150 million individuals worldwide. Maintenance of
near-normal glucose control in patients with type 2 diabetes
been shown to be associated with a reduced risk of microvascular
complications as well as a trend toward reduction of macrovascular
events. Treatment with antihyperglycemic agents is initially
successful in type 2 diabetes, but it is often associated
with a high secondary failure rate, and the addition of insulin
is eventually necessary to restore acceptable glycemic control
for many patients. The molecular reasons for the different
responses to antidiabetic therapy are not clear, and the possibility
that genetic factors may predispose to failure to respond
adequately to oral antidiabetic agents remains an open question.
Pharmacogenetics is an emerging discipline that involves the
search for genetic polymorphisms, commonly observed among
the general population, which influence drug response. Interesting
candidate genes belong to three main groups: 1) genes encoding
for drug metabolizing enzymes and/or transporters that influence
pharmacokinetics; 2) genes encoding for targets and/or receptors
of drugs that influence pharmacodynamics; and 3) genes encoding
for proteins that are involved in the causal pathway of disease
and are able to modify the effects of drugs. In this review,
we will discuss our current understanding of genetic polymorphisms
that may affect responses of patients with type 2 diabetes
to antidiabetic oral treatment as well as the main challenges,
which should be addressed in order to translate pharmacogenetics
principles into widespread clinical practice.
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