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Current Pharmacogenomics
ISSN: 1570-1603
Current Pharmacogenomics
Volume 3, Number 1, March 2005
Contents
Saccharomyces Cerevisiae as a Genetic Model in Anticancer
Therapy Pp.1-7
J.E. Kurtz, P. Dufour, J.P. Bergerat and F. Exinger
[Abstract] [Full
text article]
The Genetic Regulation of ADPRT/PARP-1 in Aging and Cancer
Susceptibility Pp.9-19
Kristin L. Lockett, Isaac V. Snowhite, and Jennifer J.
Hu
[Abstract] [Full
text article]
Bilirubin and the Genome: The Hereditary Basis of Unconjugated
Neonatal Hyperbilirubinemia Pp.21-42
Michael Kaplan and Cathy Hammerman
[Abstract] [Full
text article]
Influence of CYP2D6 Genetics on Opioid Kinetics, Metabolism
and Response Pp.43-52
Gerd Mikus and Johanna Weiss
[Abstract] [Full
text article]
Multigenic Control of Drug Response and Regulatory Decision-Making
in Pharmacogenomics: The Need for an Upper-Bound Estimate
of Genetic Contributions Pp.53-71
V. Ozdemir, W. Kalow, L. Tothfalusi, L. Bertilsson, L.
Endrenyi, J.E. Graham
[Abstract] [Full
text article]
DNA Methylation in the Pathogenesis of Systemic Lupus Erythematosus
Pp.73-78
Amr H. Sawalha and Bruce Richardson
[Abstract] [Full
text article]
Abstracts
[Back to top]
Saccharomyces Cerevisiae as a Genetic Model in
Anticancer Therapy
J.E. Kurtz, P. Dufour, J.P. Bergerat and F. Exinger
[Full text article]
With the recent sequencing of its entire genome, the yeast
Saccharomyces cerevisiae has gained considerable
interest in the field of anticancer research. The genetic
properties of the yeast allow easy selection of a variety
of mutants, as their related phenotypes provide valuable information
on anticancer drugs effects in vivo. Moreover, the
yeast has been extensively studied as a model system to decipher
basic cellular processes that are well conserved from yeast
to human and implicated in cancer establishment and progression.
We discuss the advantages of Saccharomyces cerevisiae
for investigating the metabolism of pyrimidines, a major target
for anticancer chemotherapy. We also emphasize the links between
basic science in the pyrimidine metabolism and new anticancer
antimetabolites as well as future prospects in this field.
[Back to top]
The Genetic Regulation of ADPRT/PARP-1 in Aging and Cancer
Susceptibility
Kristin L. Lockett, Isaac V. Snowhite, and Jennifer J.
Hu
[Full text article]
The ADP-ribosyltransferase (ADPRT) gene encodes the poly(ADP-ribose)polymerase-1
(PARP-1) enzyme, which plays critical roles in DNA-damage
signaling and repair, cell death, maintenance of genomic stability,
and carcinogenesis. It may also serve as a potential target
for cancer therapy. In this review, we evaluate findings from
animal model systems and molecular epidemiological studies
to demonstrate the potential role of ADPRT/PARP-1 in aging
and carcinogenesis. With increasing interest in associating
human cancer risk with single nucleotide polymorphisms (SNPs)
and/or dysfunction of ADPRT/PARP-1, several important technical
challenges will need to be overcome. These challenges include
developing specific functional assays, selecting SNPs with
potential functional impact, and exploring statistical methods
for gene-gene and gene-environmental interactions. Therefore,
this review also highlights strategies to evaluate the functional
significance of ADPRT/PARP-1 SNPs in human cancer
risk assessment. In summary, dysfunction of PARP-1 may play
a critical role in abnormal cellular functions; its molecular
mechanism in aging and cancer susceptibility is an issue which
needs urgently to be elucidated.
[Back to top]
Bilirubin and the Genome: The Hereditary Basis of Unconjugated
Neonatal Hyperbilirubinemia
Michael Kaplan and Cathy Hammerman
[Full text article]
Severe neonatal unconjugated hyperbilirubinemia, with the
risk of bilirubin encephalopathy or kernicterus in severe,
untreated cases, occurs when bilirubin production exceeds
the body's ability to eliminate it. The causes of neonatal
hyperbilirubinemia are multifactorial and comprise increased
hemolysis on the one hand, and diminished bilirubin conjugation
on the other. In recent years, many of these etiologies have
been found to have a genetic origin. Sometimes hereditary
factors act independently, but in other circumstances, single
mutations which ordinarily do not produce disease in and of
themselves, may result in severe hyperbilirubinemia as a result
of interaction with other mutated genes. Of cardinal importance
to this discussion is the concept of the human genome, whereby
the thousands of genes of which it is comprised may interact
one with the other, or with the environment, exacerbating
the severity of jaundice in certain individuals, and protecting
against hyperbilirubinemia in others. Genetic interactions
have been demonstrated combining increased bilirubin production
with diminished bilirubin conjugation, resulting in severe
hyperbilirubinemia. Appreciation of the multiplicity of genetic
interactions is of importance in our evaluation of the neonate
with severe hyperbilirubinemia, in our attempts to prevent
future cases of kernicterus, and in genetic counseling of
families who have had an infant with severe neonatal hyperbilirubinemia.
Gene therapy for the most severe of these inherited defects
of bilirubin conjugation, Crigler-Najjar syndrome type 1,
might become a reality in future years.
[Back to top]
Influence of CYP2D6 Genetics on Opioid Kinetics, Metabolism
and Response
Gerd Mikus and Johanna Weiss
[Full text article]
Pharmacogenetics does seem to play a key role in the use
of so-called weak opioids. It has been shown for codeine,
dihydrocodeine, oxycodone and hydrocodone, that their O-demethylation
in the 3-position results in metabolites which have much stronger
µ-receptor binding. These opioids may therefore exert
their pharmacological actions predominantly through their
O-demethylated metabolites. However, this metabolic step is
under genetic control of the polymorphic cytochrome P450 2D6
isozyme (CYP2D6). Poor metabolisers of CYP2D6 (~10% of the
Caucasian population) do not express this enzyme and hence
can only form trace amounts of the O-demethylated metabolites
of these four opioids. This might put these persons on risk
of reduced or even abolished analgesic effects when given
these weak opioids. From this point of view there are two
major issues why weak opioids cannot wholeheartedly be recommended:
large interindividual variability of the analgesic effect
due to CYP2D6 polymorphism and 10% of patients with no benefit
from these drugs. On the other hand it might be advantageous
to use the O-demethylated metabolites morphine, oxymorphone
and hydromorphone which are all strong opioids and have a
smaller interindividual variability of the opioid effects.
Instead of using weak opioids, small doses and controlled
release formulations of strong opioids might be the future
way to in analgesic therapy despite the fear of addiction
and bureaucratic efforts involved with these compounds.
[Back to top]
Multigenic Control of Drug Response and Regulatory Decision-Making
in Pharmacogenomics: The Need for an Upper-Bound Estimate
of Genetic Contributions
V. Ozdemir, W. Kalow, L. Tothfalusi, L. Bertilsson, L.
Endrenyi and J.E. Graham
[Full text article]
Nature or nurture? To what extent genetics play a role in
drug efficacy and safety? These questions are not new. They
are however gaining increasing prominence with the implementation
of pharmacogenomics in various facets of medicine ranging
from therapeutics, drug development and regulatory science
to research funding decisions. For predisposition to common
complex diseases, twin and family studies have been the mainstay
for estimating genetic components of the attendant risk. On
the other hand, the rapid pace of drug development in the
pharmaceutical industry and the need for faster regulatory
decisions call for an approach of higher throughput to identify
the compounds for which heritability is likely to play a significant
role in their pharmacokinetics and/or pharmacodynamics. A
second predicament related to multifactorial nature of drug
effects is that one typically observes a considerable overlap
in the distribution of drug response phenotypes among subpopulations
identified by each pharmacogenomic biomarker. This is in sharp
contrast to monogenic pharmacological traits wherein it is
feasible to partition the patient populations into discrete
subgroups by analysis of a single gene. Hence, as pharmacogenomic
investigations progress from monogenic to increasingly multigenic
or multifactorial drug response phenotypes, the regulatory
decision-makers are faced with a dilemma: How can a reviewer
or a clinician determine if a given separation of a drug response
profile by a pharmacogenomic biomarker is worthwhile for clinical
implementation? The present manuscript makes an attempt to
address these broad and emerging issues in pharmacogenomics
and regulatory science. We propose that a comparison of inter-
versus intra-subject variability in drug response under minimal
environmental exposure may provide an upperbound estimate
of heritability of drug efficacy and safety. It is also argued
that seemingly modest changes in population averages may underestimate
the dramatic impact of a genetic biomarker at the tails of
a population. To this end, a conceptual framework for graded
risk assessment among subpopulations with overlapping quantitative
phenotypes is presented. We conclude with a broader discussion
of the evolution of genetic biomarkers from monogenic to multigenic
traits in pharmacology, the associated ethical, social and
therapeutic policy corollaries and the challenges lying ahead.
[Back to top]
DNA Methylation in the Pathogenesis of Systemic Lupus Erythematosus
Amr H. Sawalha and Bruce Richardson
[Full text article]
Some forms of drug-induced lupus may be due to inhibition
of T cell DNA methylation. DNA methylation modifies gene expression.
In general, methylation of regulatory elements suppresses
gene expression, while hypomethylation promotes gene expression.
Methylation patterns are replicated during mitosis by a family
of DNA methyltransferases, whose expression is regulated in
part by signals transmitted through the extracellular signal-regulated
kinase (ERK) pathway. Inhibition of DNA methylation during
mitosis results in aberrant gene expression in the daughter
cells, sometimes with pathologic consequences. A recent series
of reports demonstrates that treating T lymphocytes with DNA
methyltransferase inhibitors such as 5-azacytidine and procainamide,
or ERK pathway inhibitors including hydralazine and the MEK
inhibitor U0126, inhibits DNA methylation, alters gene expression,
and induces autoreactivity. The autoreactive cells cause a
lupus-like disease in animal models. Importantly, the same
DNA sequences are demethylated in T cells from patients with
active lupus, with identical effects on gene expression. These
observations suggest that certain drugs and chemicals, and
possibly as yet unidentified environmental toxins, can modify
DNA methylation patterns through effects on DNA methyltransferase
activity or expression, resulting in disordered gene expression
and the subsequent development of a lupus-like disease.
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