| Current
Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 5, Number 1, March 2007
Contents
Effects of Polymorphisms of the CYP450 Enzyme
Genes on Estrogen Status and the Risk for Osteoporosis
Pp. 1-10
N. Napoli and R. Armamento-Villareal
[Abstract] [Full
text article]
Chemogenomics of Sensitivity and Resistance to
Anticancer Drugs Pp. 11-19
Z. Dai, W. Sadee and P. Blower
[Abstract] [Full
text article]
Metabotropic Glutamate Receptor Genes as Candidates
for Pharmacogenetic Studies of Current and Future Antipsychotic
Agents in Schizophrenia Pp. 21-30
J.R. Bishop and V.L. Ellingrod
[Abstract] [Full
text article]
Pharmacogenetic Syndrome of Dihydropyrimidine Dehydrogenase
Deficiency Pp. 31-38
H.-H. Hsiao and S.-F. Lin
[Abstract] [Full
text article]
Gold Nanoparticle Based Systems in Genetics
Pp. 39-47
J.F. Gaspar, P.V. Baptista and J. Rueff
[Abstract] [Full
text article]
Genetic Polymorphisms and Haplotypes of Major Drug
Metabolizing Enzymes in East Asians and Their Comparison with
Other Ethnic Populations Pp. 49-78
Y. Saito, K. Maekawa, S. Ozawa and J. Sawada
[Abstract] [Full
text article]
Pathway-based Approaches to Pharmacogenomics
Pp. 79-86
C.F. Thorn, M. Whirl-Carrillo, T.E. Klein and R.B. Altman
[Abstract] [Full
text article]
Abstracts
[Back to top]
Effects of Polymorphisms of the CYP450 Enzyme Genes on Estrogen
Status and the Risk for Osteoporosis
N. Napoli and R. Armamento-Villareal
[Full
text article]
Several enzymes belonging to the CYP450 group are involved
in the biosynthesis and metabolism of estrogen. Polymorphisms
of the genes encoding for these enzymes have been linked to
hormone-related diseases, notably breast cancer. These associations
are based on the notion that certain variants of these enzymes
have altered activity resulting in an alteration in estrogenic
state, which in turn leads to differences in the risk for
hormone-related disorders. Recent studies have indicated that
these same polymorphisms are also important determinants of
bone mineral density (BMD) and osteoporosis, another hormone-dependent
condition. To name some, certain polymorphisms in the CYP19,
CYP17, CYP1A1 and CYP1B1 genes have been found to affect BMD.
So far, in this context, the most extensively investigated
polymorphisms are those of the CYP19, the gene that codes
for aromatase, an important enzyme in the estrogen biosynthetic
pathway that converts androgenic steroids to estrogen. To
our knowledge, four important polymorphisms of the aromatase
gene are associated with differences in BMD and the risk for
osteoporosis. Newer data further suggest that response to
estrogen or hormone therapy may also be influenced by polymorphisms
in the aromatase gene. And finally, a recent report indicates
that polymorphisms of the genes encoding for the enzymes that
metabolize estrogen are also important determi-nants of BMD.
The C4887A polymorphism in the CYP1A1 gene is found to be
associated with increased estrogen catabolism and lower femoral
BMD in women carrying the A allele, present in 19% of the
population. A similar (unpublished) observation is also noted
for one of the CYP1B1 gene polymorphisms. The main focus of
this review is to examine the effects of polymorphisms of
the CYP 450 enzyme genes involved in estrogen biosynthesis
and metabolism on BMD and the risk for osteoporosis.
[Back to top]
Chemogenomics of Sensitivity and Resistance to
Anticancer Drugs
Z. Dai, W. Sadee and P. Blower
[Full
text article]
Chemogenomics integrates genomic datasets with biological
and chemical characteristics of compounds. It uses genomic
or proteomic profiling combined with chemoinformatics and
statistics to study the response of a biological system to
chemical compounds. This large-scale approach is particularly
suitable for addressing chemotherapeutic resistance, a main
obstacle to successful treatment of cancer patients. Chemogenomics
as a discipline has been molded by a suite of datasets derived
from a panel of 60 cancer cell lines that are used for drug
discovery by the National Cancer Institute (NCI-60). Offering
cytotoxic potencies for >50,000 compounds across the NCI-60,
and mRNA profiles, proteomes, mutations, and epigenetic factors,
this unparalleled public resource enables rapid discovery
of molecular targets and mechanisms of chemosensitivity/resistance.
While chemogenomics holds much promise, broader impact in
all fields of biology and medicine requires expansion of curated
and accessible datasets of diverse biological systems, biological
and chemical properties of compound libraries, and novel informatics
tools for extracting the valuable information embedded in
high-dimensional data. Exploiting the effects of diverse chemical
probes, chemogenomics adds an important dimension to systems
biology for understanding cellular functions.
[Back to top]
Metabotropic Glutamate Receptor Genes as Candidates
for Pharmacogenetic Studies of Current and Future Antipsychotic
Agents in Schizophrenia
J.R. Bishop and V.L. Ellingrod
[Full
text article]
Recent research has linked the polymorphic metabotropic glutamate
receptors to the pathogenesis of schizophrenia contributing
to the development of the “glutamate hypothesis”.
These receptors regulate glutamate through NMDA inotropic
receptors. At the neurotransmitter level, antipsychotics developed
to treat schizophrenia have been found to significantly increase
serum glutamate levels and potentially affect the expression
of various metabotropic glutamate receptors (mGluRs). Additionally,
type-3 metabotropic glutamate receptor gene (GRM3)
polymorphisms have been associated with schizophrenia as well
as being linked to reductions in prefrontal cortex N-acetylaspartate
concentrations. Thus, glutamate has become an increasingly
important area of interest for therapeutic intervention in
schizophrenia and pharmaceutical companies are rapidly focusing
on the development of agents that directly modulate this neurotransmitter;
however the reality is that the clinical use of such drugs
is still years away. Taken together, investigations of how
genetic variability in genes coding for mGluRs relate to treatment
outcomes are becoming increasingly important. The goal of
this review is to discuss the genetics, pharmacology, and
pharmacogenetics of the metabotropic glutamate receptors focusing
on receptor subtypes with the most evidence for involvement
with current and/or future antipsychotic activity.
[Back to top]
Pharmacogenetic Syndrome of Dihydropyrimidine Dehydrogenase
Deficiency
H.-H. Hsiao and S.-F. Lin
[Full
text article]
Dihydropyrimidine dehydrogenase (DPD), which is the initial
and rate-limiting enzyme of the degradation of pyrimidine
base, plays an important role in the pharmacogenetic syndrome
of 5-fluorouracil (5-FU). Deficiency of DPD activity leads
to severe toxicities, even death, in patients after administering
5-FU. Several studies demonstrate that the molecular defects
of the dihydropyrimidine dehydrogenase gene (DPYD)
lead to the deficiency of DPD activity and cause this pharmacogenetic
syndrome. However, polymorphic DPD activity and complex nature
of the DPYD sometimes result in conflicting findings.
To date, more than 40 variant alleles, including 2 splice-site
mutations, 2 nonsense mutations, 5 deletion mutations, 32
missense mutations and 2 slice mutations have been reported
in the coding area of the DPYD gene. The IVS14+1G>A,
which leads to the skipping of the exon 14 resulting in profound
DPD deficiency and severe toxicities, is the most common mutation
with 5-FU toxicity in Europeans. In addition, the epigenetic
factors also participate in the clinical presentations of
the syndrome. Due to the fact that the regulation mechanism
of DPD itself has not been clearly clarified yet, high-throughput
techniques to screen the whole DPYD and the measurement
of the DPD activity are warranted to draw a clear relationship
between the phenotype and genotype for this pharmacogenetic
syndrome. Screening for genetic DPYD defects, at
least IVS14+1G>A, and/or the DPD activity before 5-FU therapy
to protect patients from hazardous outcome is also suggested,
especially in specific populations.
[Back to top]
Gold Nanoparticle Based Systems in Genetics
J.F. Gaspar, P.V. Baptista and J. Rueff
[Full
text article]
Advances in nanoscience are having a significant impact on
many scientific fields, boosting the development of a variety
of important technologies. The impact of these new technologies
is particularly large in biodiagnostics, where a number of
nanoparticle-based assays have been introduced for biomolecular
detection. The physicochemical malleability and high surface
areas of nanoparticle surfaces make them ideal candidates
for developing biomarker platforms. Given the variety of strategies
afforded through nanoparticle technologies, a significant
goal is to tailor nanoparticle surfaces to selectively bind
a subset of biomarkers, either for direct detection and characterization
or to sequester the target molecules for later study using
other available techniques. To date, applications of nanoparticles
have largely focused on DNA- or protein-functionalized gold
nanoparticles used as the target-specific probes. These unique
biophysical properties displayed by gold nanoparticles have
huge advantages over conventional detection methods (e.g.,
molecular fluorophores, microarray technologies). These gold-nanoparticle
based systems can then be used for the detection of specific
sequences of DNA (pathogen detection, characterization of
mutation and/or SNPs) or RNA (without previous retro-transcription
and amplification).
[Back to top]
Genetic Polymorphisms and Haplotypes of Major Drug
Metabolizing Enzymes in East Asians and Their Comparison with
Other Ethnic Populations
Y. Saito, K. Maekawa, S. Ozawa and J. Sawada
[Full
text article]
Remarkable ethnic differences in drug response are well known,
and many of these can be attributed to differences in genetic
backgrounds. Accumulating evidence has shown that genetic
polymorphisms can cause the alteration or even loss of activity
in drug metabolizing enzymes, transporters and receptors.
Thus, genetic polymorphisms may be important in understanding
these ethnic differences in drug response. Furthermore, haplotypes,
linked combinations of genetic polymorphisms on a chromosome,
have the advantage of providing more useful information on
phenotype–genotype links than individual polymorphisms.
In the past 6 years, mostly as a Japanese national project,
we resequenced the exons and enhancer/promoter regions of
more than 30 drug metabolizing enzymes, transporters and receptors
using genomic DNA from 100 to 500 Japanese subjects, analyzed
linkage-disequilibrium (LD), and estimated haplotype structures.
Regarding CYP2C9 and 2C19, we found linkages
between CYP2C19*2 or *3 and CYP2C9*1,
and between CYP2C9*3 and CYP2C19*1 haplotypes.
Haplotype structures of CYP2D6 are complicated by
gene duplication or recombination. In contrast, the haplotype
structure of CYP3A4 was simple, but close linkages
were observed with other CYP3As. As for UGT1As,
the 8 first exons encoding active isoforms and common exons
2-5 were divided into 5 blocks by LD analysis, and intra-
and inter-block haplotypes were estimated. Several linkages
of haplotypes with functional importance were revealed, such
as UGT1A7*3 - UGT1A6*2 - UGT1A1*28 or *6.
In this review, we summarize polymorphisms and haplotype structures
of these clinically important drug metabolizing enzymes in
East Asians, mainly from our Japanese data, and compare them
with those of other ethnicities.
[Back to top]
Pathway-based Approaches to Pharmacogenomics
C.F. Thorn, M. Whirl-Carrillo, T.E. Klein and R.B. Altman
[Full
text article]
Researchers are using pathway information for both
pharmacogenomics study design and data analysis. Candidate
gene approaches for the design of pharmacogenomic studies
need reliable pathway information to choose the best candidate
genes and SNPs, especially when using low to medium throughput
genotyping technologies, to maximize the likelihood of success.
With the mainstream use of high throughput gene expression
microarrays and genome wide SNP assays, pathway-based approaches
can also be valuable tool for data analysis. This review will
discuss sources of pathway data and mechanisms for applying
it to pharmacogenomics research.
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