|
Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 9, Number 6, July 2008
Contents:
N-Acetyltransferases: Lessons Learned from Eighty
Years of Research
Guest Editor: José A.G. Agúndez
Editorial Pp. 463-464
Structures of Human Arylamine N-Acetyltransferases
Pp. 465-470
D.M. Grant
[Abstract]
Structure/Function Evaluations of Single Nucleotide Polymorphisms
in Human N-Acetyltransferase 2 Pp. 471-486
J.M. Walraven, Y. Zang, J.O. Trent and D.W.
Hein
[Abstract]
Interethnic and Intraethnic Variability of NAT2 Single Nucleotide
Polymorphisms Pp. 487-497
Elena García-Martín
[Abstract]
Regulation of Arylamine N-Acetyltransferases Pp.
498-504
N.J. Butcher, J. Tiang and R.F. Minchin
[Abstract]
Effect of Environmental Substances on the Activity of Arylamine
N-Acetyltransferases Pp. 505-509
F. Rodrigues-Lima, J. Dairou and J.M. Dupret
[Abstract]
Arylamine N-Acetyltransferases in Mycobacteria Pp.
510-519
E. Sim, J. Sandy, D. Evangelopoulos, E. Fullam,
S. Bhakta, I. Westwood, A. Krylova, N. Lack and M. Noble
[Abstract]
Polymorphisms of Human N-Acetyltransferases and Cancer
Risk Pp. 520-531
J.A.G. Agúndez
[Abstract]
Influence of Polymorphic N-Acetyltransferases on Non-Malignant
Spontaneous Disorders and on Response to Drugs Pp.
532-537
J.M. Ladero
[Abstract]
Human N-Acetyltransferases and Drug-Induced Hepatotoxicity
Pp. 538-545
S.I. Makarova
[Abstract]
N-Acetyltransferases as Markers for Asthma and Allergic/Atopic
Disorders Pp. 546-553
J. Batra and B. Ghosh
[Abstract]
General Articles
Drug Eluting Stents: Friend or Foe? A Review
of Cellular Mechanisms Behind the Effects of Paclitaxel and
Sirolimus Eluting Stents Pp. 554-566
S. Chatterjee and A. Pandey
[Abstract]
Using Bioinformatics Techniques for Gene Identification
in Drug Discovery and Development Pp. 567-573
Y.-P. Phoebe Chen and F. Chen
[Abstract]
Predicting the Volume of Distribution of Drugs in
Humans Pp. 574-580
X. Sui, J. Sun, X. Wu, H. Li, J. Liu and Z. He
[Abstract]
Abstracts
[Back to top]
Editorial
During the past 80 years, research on Arylamine-Nacetyltransferases
(CoASAc; NAT, EC 2.3.1.5) has produced many major discoveries
that have helped scientists understand the basis for altered
metabolism of drugs and xenobiotics.
The first references to the relevance of N-acetylation in
humans date back to 1926 [1]. Nearly fifty years ago, Evans
et al. demonstrated that acetylation of the isoniazid
was bimodally distributed and that in vivo acetylation
status was inheritable [2, 3]. The milestone work carried
out by Meyer et al. in the Biozentrum of the University
of Basel around 1990 caused a dramatic impulse in present
knowledge of N-Acetyltransferases. This work included the
demonstration that common polymorphisms in human NAT2 result
in a decreased level of protein in the liver [4], the partial
purification of human NAT2 [5], the cloning of NAT1 and NAT2
[5, 6] and the functional analysis of recombinant expressed
protein products [4]. Further developments in the role of
polymorphisms on NAT2 activity were carried out by Hein
et al. [7], and it is not surprising that the number
of publications on N-acetyltransferases increased sharply
from an average of 30-50 publications per year before 1990
to about 300 publications per year after 1991. Sinclair et
al. in 2000 provided the first crystal structure of a
NAT protein [8] and recently high resolution crystal structures
of human NAT1 and NAT2 have been solved [9], revealing prominent
features of NAT enzymes that will be of great help to further
studies on structure, function and clinical relevance of NAT
enzymes.
The complexity of variations in NAT1 and NAT2
genes has put NAT in the forefront of pharmacogenetics research.
Four decades after the recognition and effect of NAT2
polymorphism on isoniazide toxicity [10], present genotyping
techniques allow the detection of major genetic variations
in these genes and permit acetylation phenotypes to be inferred
from genotyping data by using bioinformatic tools [11]. The
determination of the NAT2 genotype or phenotype was initially
proposed to predict adverse reactions in patients with tuberculosis
receiving isoniazid [12], before the concomitant administration
of procainamide and phenytoin [13], and to analyze the role
of NAT2 in drug interactions [14]. These effects together
with the high frequency for individuals with impaired NAT2
metabolism [4] make NAT2 a relevant target for pharmacogenomic
tests in clinical practice. Since NAT gene polymorphisms
have been considered as putative risk factors for some xenobiotic-related
cancers because of the prominent role of NAT enzymes in drug
and carcinogen activation and detoxification, we can now take
advantage of these pharmacogenomic tests to assess cancer
risk and the risk of other human diseases. Presently, research
on Arylamine-N-acetyltransferases constitutes a major topic
in pharmacology and pharmacogenomics and has therapeutic,
preventive, anthropologic and even forensic implications.
The bibliometric impact of Arylamine-N-acetyltransferases
is impressive. In recent years, over 5,000 papers related
to drug acetylation and NAT polymorphisms have been published.
These papers accumulate over 100,000 citations and an h-index
over 120. Nowadays an average of six articles on this topic
are published per week. This special issue of Current Drug
Metabolism on N-acetyltransferases provides a collection of
review articles covering relevant basic and clinical topics
in which NATs are of prominent relevance. The articles presented
summarize the present knowledge of these topics, and identify
further aspects that should be investigated in detail.
The topics covered include the most recent advances in the
structure of human NATs obtained after crystallization and
direct structural analysis of human NAT1 and NAT2 as well
as the potential applications of this information to the prediction
of therapeutic and toxic effects [15]. A collection of papers
related to genetic and non-genetic factors influencing NAT
activities is also included in this special issue. The first
of such papers is a comprehensive review of structure-function
of variant NAT2 enzymes, including an analysis and molecular
modeling of the effects of individual single nucleotide polymorphisms
(SNPs) on NAT2 function and an update on NAT2 allele
nomenclature [16]. The interethnic variability of human NAT2
SNPs, obtained after deconstruction of inferred variant alleles
to avoid confounders, is analyzed in another paper that unravels
the occurrence of intraethnic variability in NAT2 SNP frequencies
and discusses the potential clinical impact of such intraethnic
variability [17]. Besides genetic factors, other factors are
involved in the regulation and function of NAT enzymes. These
factors are analyzed in detail in two review papers: the first
one focuses on non-genetic control of NAT expression, including
transcriptional, post-transcriptional/translational, and post-translational
regulation [18], and the second one deals with substrate-dependent
inhibition, drug interactions or other factors that may also
contribute to variations of NAT activity [19]. Current knowledge
of N-Acetyltransferases in mycobacteria, an enzyme
involved in isoniazid inactivation, including genetic variations
and endogenous role, is discussed in another review paper
[20]. The last part of the special issue is composed of four
review papers which analyze current knowledge of the clinical
potential of NATs. These include a review paper on the role
of NATs in human cancer risk that identifies relevant associations
of NAT polymorphisms and human cancer risk; it also
describes controversial findings, putative causes of heterogeneity
in the proposed associations and topics that require further
investigation [21]. A second review paper analyzes the role
of NAT polymorphisms in non-malignant spontaneous
disorders, including dysimmune or degenerative diseases as
well as drug response [22]. The potential role of NAT
in drug-induced hepatotoxicity is further analyzed in another
review paper [23], and a final paper is devoted to analysis
of the role of NATs as a potential marker for asthma or other
allergic diseases [24].
Further advancements in NAT research can be expected by combining
basic and clinical information on NATs, and with the combined
information obtained from proteomics, genomics, bioinformatics
and pharmacology. We hope that in the next few years the impressive
research effort dedicated to NATs will result in widely used
tools capable of increasing the efficiency and safety of drug
therapy with NAT substrates, and/or to identify individuals
with increased susceptibility to neoplastic or other disorders
related to NATs or to interaction of NATs with dietary or
environmental factors. In the hope that the dramatic increase
in the knowledge of NATs in recent years will result in clinically
relevant advances in individualized medicine, I would like
to thank, as Guest Editor of the special issue of Current
Drug Metabolism, all the authors who kindly contributed to
this issue.
REFERENCES
[1] Muenzen, J. B.; Cerecedo, L. R. and Shervin, C. P. (1926)
J. Biol. Chem., 67, 469-476.
[2] Evans, D. A.; Manley, K. A. and Mc, K. V. (1960) Br.
Med. J., 2, 485-491.
[3] Evans, D. A.; Storey, P. B.; Wittstadt, F. B. and Manley,
K. A. (1960) Am. Rev. Respir. Dis., 82,
853-861.
[4] Blum, M.; Demierre, A.; Grant, D. M.; Heim, M. and Meyer,
U. A. (1991) Proc. Natl. Acad. Sci. USA, 88,
5237-5241.
[5] Grant, D. M.; Blum, M.; Demierre, A. and Meyer, U. A.
(1989) Nucleic. Acids. Res., 17,
3978.
[6] Blum, M.; Grant, D. M.; McBride, W.; Heim, M. and Meyer,
U. A. (1990) DNA Cell. Biol., 9,
193-203.
[7] Hein, D. W.; Ferguson, R. J.; Doll, M. A.; Rustan, T.
D. and Gray, K. (1994) Hum. Mol. Genet., 3,
729-734.
[8] Sinclair, J. C.; Sandy, J.; Delgoda, R.; Sim, E. and Noble,
M. E. (2000) Nat. Struct. Biol., 7,
560-564.
[9] Wu, H.; Dombrovsky, L.; Tempel, W.; Martin, F.; Loppnau,
P.; Goodfellow, G. H.; Grant, D. M. and Plotnikov, A. N. (2007)
J. Biol. Chem., 282, 30189-30197.
[10] Weber, W. W. and Cohen, S. N. (1968) Biochim. Biophys.
Acta, 151, 276-278.
[11] Agundez, J. A.; Golka, K.; Martinez, C.; Selinski, S.;
Blaszkewicz, M. and Garcia-Martin, E. (2008) Clin. Chem.,
in press.
[12] Clark, D. W. (1985) Drugs, 29,
342-375.
[13] Crook, J. E.; Woosley, R. L.; Leftwich, R. B. and Natelson,
E. A. (1979) South Med. J., 72,
1599-1601.
[14] Colmenero, J. D.; Fernandez-Gallardo, L. C.; Agundez,
J. A.; Sedeno, J.; Benitez, J. and Valverde, E. (1994)
Antimicrob. Agents Chemother., 38, 2798-2802.
[15] Grant, D. M. (2008) Curr. Drug Metab., in press.
[16] Walraven, J. M.; Zang, Y.; Tren, J. O. and Hein, D. W.
(2008) Curr. Drug Metab., in press.
[17] Garcia-Martin, E. (2008) Curr. Drug Metab.,
in press.
[18] Butcher, N. J.; Tiang, J. and Minchin, R. F. (2008) Curr.
Drug Metab., in press.
[19] Rodrigues-Lima, F.; Dairou, J. and Dupret, J. M. (2008)
Curr. Drug Metab., in press.
[20] Sim, E.; Sandy, J.; Evangelopoulos, D.; Fullam, E.; Bhakta,
S.; Westwood, I.; Krylova, A.; Lack, N. and Noble, M. (2008)
Curr. Drug Metab., in press.
[21] Agundez, J. A. (2008) Curr. Drug Metab., in
press.
[22] Ladero , J. M. (2008) Curr. Drug Metab., in
press.
[23] Makarova, S. I. (2008) Curr. Drug Metab., in
press.
[24] Batra, J. and Gosh, B. (2008) Curr. Drug Metab.,
in press.
José A.G. Agúndez
Department of Pharmacology
Medical School
University of Extremadura
Avda. de Elvas s/n
E-06071, Badajoz
Spain
[Back to top]
Structures of Human Arylamine N-Acetyltransferases
D.M. Grant
A large body of biochemical, kinetic and molecular information,
accumulated over the course of more than 80 years, has produced
valuable insights into the relationship between the structures
and the catalytic functions of the human arylamine N-acetyltransferases
NAT1 and NAT2. Much of the groundwork for the determination
of human NAT structures and functions was provided by seminal
biochemical and enzyme kinetic studies in both human and non-human
model systems, the cloning and primary amino acid sequence
determination of eukaryotic and prokaryotic NATs, the characterization
of naturally occurring and artificially mutated forms of human
NATs, elucidation of the crystal structures of several prokaryotic
NAT orthologues, and information that has been derived from
cross-species comparisons. In 2007 the progress of these studies
was aided substantially by the successful crystallization
and direct structural analysis of human NAT1 and NAT2. The
purpose of this review is to give a brief historical perspective,
to summarize our current understanding of human NAT structures
and functions based on both earlier and more recent work,
and to provide some future insights into the potential applications
of this information to the prediction of therapeutic and toxic
outcomes associated with the acetylation of primary aromatic
amine- and hydrazine-containing chemicals.
[Back to top]
Structure/Function Evaluations of Single Nucleotide Polymorphisms
in Human N-Acetyltransferase 2
J.M. Walraven, Y. Zang, J.O. Trent and D.W.
Hein
Arylamine N-acetyltransferase 2 (NAT2) modifies drug efficacy/toxicity
and cancer risk due to its role in bioactivation and detoxification
of arylamine and hydrazine drugs and carcinogens. Human NAT2
alleles possess a combination of single nucleotide polymorphisms
(SNPs) associated with slow acetylation phenotypes. Clinical
and molecular epidemiology studies investigating associations
of NAT2 genotype with drug efficacy/toxicity and/or
cancer risk are compromised by incomplete and sometimes conflicting
information regarding genotype/phenotype relationships. Studies
in our laboratory and others have characterized the functional
effects of SNPs alone, and in combinations present in alleles
or haplotypes. We extrapolate this data generated following
recombinant expression in yeast and COS-1 cells to assist
in the interpretation of NAT2 structure. Whereas previous
structural studies used homology models based on templates
of N-acetyltransferase enzyme crystal structures from various
prokaryotic species, alignment scores between bacterial and
mammalian N-acetyltransferase protein sequences are low (~
30%) with important differences between the bacterial and
mammalian protein structures. Recently, the crystal structure
of human NAT2 was released from the Protein Data Bank under
accession number 2PFR. We utilized the NAT2 crystal structure
to evaluate the functional effects of SNPs resulting in the
protein substitutions R64Q (G191A), R64W (C190T), I114T (T341C),
D122N (G364A), L137F (A411T), Q145P (A434C), E167K (G499A),
R197Q (C590A), K268R (A803G), K282T (A845C), and G286E (G857A)
of NAT2. This analysis advances understanding of NAT2 structure-function
relationships, important for interpreting the role of NAT2
genetic polymorphisms in bioactivation and detoxification
of arylamine and hydrazine drugs and carcinogens.
[Back to top]
Interethnic and Intraethnic Variability of NAT2 Single Nucleotide
Polymorphisms
Elena García-Martín
Genetic polymorphisms of human arylamine N-acetyltransferase
2 (NAT2) are responsible for interindividual variation in
the acetylation of numerous drugs and in the transformation
of aromatic and heterocyclic amines into carcinogenic intermediates.
Although large interethnic variability in the frequency for
NAT2 variant alleles has been reported, comparison
of allele frequencies is hampered by differences in the criteria
for the assignment of allelic variants. To avoid such sources
of bias, in this review we analyze the occurrence of both
interethnic and intraethnic variability for the seven commonest
single nucleotide polymorphisms (SNP) in the NAT2
gene by using raw SNP data instead of inferred haplotypes.
Besides the large interethnic variability observed for all
SNPs except C282T, intraethnic variability for NAT2
SNPs was identified for the SNPs G191A among Caucasians (p<0.0001),
T341C among Oriental (p<0.001) or African individuals (p<0.012),
C481T among Oriental (p<0.001) or African individuals (p<0.001),
and G590A among Oriental individuals (p<0.001). In contrast,
no major intraethnic differences were identified for the SNPs
C282T, A806G or G857A.
Intraethnic variability may have relevant clinical implications.
For instance, case-control NAT2 studies should not
be extrapolated from one Oriental population to another. Nonsynonymous
SNPs occur in 32% of alleles in Japanese individuals and in
47% of alleles in Chinese individuals, therefore the frequency
of adverse effects and cancer related to slow acetylation
is expected to be higher in individuals with Chinese descent
than in those with Japanese descent.
Intraethnic variability reinforces the need for proper selection
of control subjects and points against the use of surrogate
control groups for studies involving association of NAT2
alleles with adverse drug effects or spontaneous diseases.
[Back to top]
Regulation of Arylamine N-Acetyltransferases
N.J. Butcher, J. Tiang and R.F. Minchin
Acetylation catalysed by the arylamine N-acetyltransferases
(NATs; 2.3.1.5) is a major biotransformation pathway for arylamine
and hydrazine drugs, as well as many carcinogens that we are
exposed to on a daily basis. These compounds can either be
detoxified by NATs or bioactivated to metabolites that have
the potential to cause toxicity such as cancer. As a result,
the levels of NATs in the body have clinical importance with
regard to drug effect and individual susceptibility to toxicity.
Like many other drug metabolising enzymes, the activity of
NATs varies considerably between individuals, due in part
to genetic polymorphisms. However, it is becoming increasingly
evident that non-genetic factors also play an important role
in regulating NAT activity in vivo. This review focuses
on the non-genetic control of NAT expression, including transcriptional,
post-transcriptional/translational, and post-translational
regulation. In addition, the dysregulation of NAT1 expression
in cancer cells is reviewed, as this is an emerging area that
may provide insight into a role for NAT1 in cancer biology.
[Back to top]
Effect of Environmental Substances on the Activity of Arylamine
N-Acetyltransferases
F. Rodrigues-Lima, J. Dairou and J.M. Dupret
Arylamine N-acetyltransferases (NAT) are xenobiotic-metabolizing
enzymes responsible for the acetylation of many aromatic arylamine
and heterocyclic amines, thereby playing an important role
in both detoxification and activation of numerous drugs and
carcinogens. Two closely related isoforms (NAT1 and NAT2)
have been described in humans. NAT2 is mainly expressed in
liver and gut, whereas NAT1 is found in a wide range of tissues.
Interindividual variations in NAT genes have been
shown to be a potential source of pharmacological and/or pathological
susceptibility. In addition, there is now evidence that non
genetic factors, such as substrate-dependent inhibition, drug
interactions or cellular redox conditions may also contribute
to NAT activity. The recent findings reviewed here provide
possible mechanisms by which these environmental determinants
may affect NAT activity. Interestingly, these data could contribute
to the development of selective NAT inhibitors for the treatment
of cancer and microbial diseases.
[Back to top]
Arylamine N-Acetyltransferases in Mycobacteria
E. Sim, J. Sandy, D. Evangelopoulos, E. Fullam,
S. Bhakta, I. Westwood, A. Krylova, N. Lack and M. Noble
Polymorphic Human arylamine N-acetyl transferase (NAT2)
inactivates the anti-tubercular drug isoniazid by acetyltransfer
from acetylCoA. There are active NAT proteins encoded by homologous
genes in mycobacteria including M. tuberculosis, M. bovis
BCG, M. smegmatis and M. marinum. Crystallographic
structures of NATs from M. smegmatis and M. marinum,
as native enzymes and with isoniazid bound share a similar
fold with the first NAT structure, Salmonella typhimurium
NAT. There are three approximately equal domains and an active
site essential catalytic triad of cysteine, histidine and
aspartate in the first two domains. An acetyl group from acetylCoA
is transferred to cysteine and then to the acetyl acceptor
e.g. isoniazid. M. marinum NAT binds CoA in a more
open mode compared with CoA binding to human NAT2. The structure
of mycobacterial NAT may promote its role in synthesis of
cell wall lipids, identified through gene deletion studies.
NAT protein is essential for survival of M. bovis BCG
in macrophage as are the proteins encoded by other genes in
the same gene cluster (hsaA-D). HsaA-D degrade cholesterol,
essential for mycobacterial survival inside macrophage. Nat
expression remains to be fully understood but is co-ordinated
with hsaA-D and other stress response genes in mycobacteria.
Amide synthase genes in the streptomyces are also nat
homologues. The amide synthases are predicted to catalyse
intramolecular amide bond formation and creation of cyclic
molecules, e.g. geldanamycin. Lack of conservation of the
CoA binding cleft residues of M. mari-num NAT suggests
the amide synthase reaction mechanism does not involve a soluble
CoA intermediate during amide formation and ring closure.
[Back to top]
Polymorphisms of Human N-Acetyltransferases and Cancer
Risk
J.A.G. Agúndez
Human arylamine N-acetyltransferases (CoASAc; NAT,
EC 2.3.1.5) NAT1 and NAT2 play a key role
in the metabolism of drugs and environmental chemicals and
in the metabolic activation and detoxification of procarcinogens.
Phenotyping analyses have revealed an association between
NAT enzyme activities and the risk of developing
several forms of cancer. As genotyping procedures have become
available for NAT1 and NAT2 gene variations,
hundreds of association studies on NAT polymorphisms
and cancer risk have been conducted. Here we review the findings
obtained from these studies.
Evidence for a putative association of NAT1 polymorphism
and myeloma, lung and bladder cancer, as well as association
of NAT2 polymorphisms with non-Hodgkin lymphoma,
liver, colorectal and bladder cancer have been reported. In
contrast, no consistent evidence for a relevant association
of NAT polymorphisms with brain, head & neck,
breast, gastric, pancreatic or prostate cancer have been described.
Although preliminary data are available, further well-powered
studies are required to fully elucidate the role of NAT1
in most human can-cers, and that of NAT2 in astrocytoma,
meningioma, esophageal, renal, cervical and testicular cancers,
as well as in leukaemia and myeloma.
This review discusses controversial findings on cancer risk
and putative causes of heterogeneity in the proposed associations,
and it identifies topics that require further investigation,
particularly mechanisms underlying association of NAT
polymorphisms and risk for subsets of cancer patients with
specific exposures, putative epistatic contribution of polymorphism
for other xenobiotic-metabolising enzymes such as glutathione
S-transferases of Cytochrome P450 enzymes, and genetic plus
environmental interaction.
[Back to top]
Influence of Polymorphic N-Acetyltransferases on Non-Malignant
Spontaneous Disorders and on Response to Drugs
J.M. Ladero
Polymorphic N-acetyl transferases (NAT) 1 and
2 are involved in detoxification of xenobiotic arylamines
and hydralazines. These common environmental chemicals may
be related to the pathogenesis of many spontaneous disorders,
mainly malignancies, but also disimmune or degenerative diseases,
for which a polygenic predisposition has been suggested. Hence,
polymorphic NAT genes (NAT2 has been the
most studied one) may be low-penetrance risk genes for some
of these disorders.
Although a relation of risk may be definitely discarded for
systemic lupus erythematosus (SLE), inflammatory bowel disease
and endometriosis, more research is needed for rheumatoid
arthritis, Parkinson’s, Alzheimer’s, Behçet’s
and periodontal diseases , as current results are inconclusive
but suggest a possible relation with NAT2 polymorphism.
In diabetes mellitus the possible relation with the rapid
phenotype may be due to acquired metabolic changes and more
genotyping studies are needed.
NAT2 slow metabolizers are more prone to the side effects
of polymorphically acetylated drugs, as is the SLE-like syndrome
induced by hydralazine and procainamide, the side effects
due to sulphasalazine and the skin rash secondary to many
sulphonamides.
Future research should be based on well-designed studies,
with adequate sample sizes and homogeneous recruitment criteria,
to obviate the proliferation of small studies that are time-
and resource-consuming without offering definite answers.
[Back to top]
Human N-Acetyltransferases and Drug-Induced Hepatotoxicity
S.I. Makarova
There are a lot of pharmaceutical substances nowadays
on the market. More than 1000 drugs have been implicated in
causing liver diseases in more than one occasion. The liver
is the most massive and important internal organ of human
body. The morphological and functional integrity of the liver
is vital to the health of the human organism. Xenobiotic biotransformation
is the principal mechanism for maintaining homeostasis during
exposure of organisms to small foreign molecules, such as
drugs. Most drugs are lipophilic and they become more hydrophilic
by xenobiotic metabolizing enzymes. Arylamine N acetyltransferases
(NAT) convert aromatic amines or hydrazines to aromatic amides
and hydrazides. A lot of generally used drugs contain aromatic
amine or hydrazine groups. Drug-induced liver injury (DILI)
is the grave problem in the present world. The frequency of
DILI is 15-40 cases per 100000 persons per year with 6 % mortality
rate on average. This review is devoted to the analyses of
arylamine N-acetyltransferases role in DILI. The NAT gene
polymorphism and slow phenotype are associated with predisposition
to hepatotoxicity during drug-specific treatment. NAT activity
is changed by smoking, viral infections and variety of drugs.
It is shown that the involving of NAT in pathogenic processes
of DILI such as inflammatory or immune response, formation
reactive metabolites, oxidative stress, cholestasis.
[Back to top]
N-Acetyltransferases as Markers for Asthma and Allergic/Atopic
Disorders
J. Batra and B. Ghosh
An increasing prevalence of asthma noted worldwide has stimulated
research on the phenotypic complexity resulting from interaction
between the genetic and environmental components. Particularly,
an increase in the prevalence of allergic rhinitis and asthma
in industrialized countries indicate the importance of pulmonary
metabolism of environmental xenobiotics. The arylamine N-acetyltransferases
(NATs) are a unique family of enzymes that are involved in
the biotransformation and detoxification of hydrazine and
arylamine drugs/xenobiotics and could have a major role to
play in atopy/asthma pathogenesis. Association studies on
NAT1 and NAT2 polymorphisms focused in this
review indicate the genetic significance of slow acetylation
phenotype in bronchial and occupational asthma as well as
in other allergic diseases in different populations worldwide.
In contrast, fast acetylators have been found to have higher
susceptibility to contact allergic dermatitis. Further in-depth
research on the functional role of N- acetylation phenotype
in disease pathogenesis is the requisite of the day, so that
N-acetylation polymorphisms could serve as a genetic marker.
Also, such genetic variations may have important implications
in the efficacy of drugs for asthma treatment.
The present review also makes a comment on the role of Arylalkylamine
N-Acetyltransferase, an important enzyme involved in the conversion
of serotonin to melatonin, in asthma pathogenesis.
[Back to top]
Drug Eluting Stents: Friend or Foe? A Review of Cellular Mechanisms
Behind the Effects of Paclitaxel and Sirolimus Eluting Stents
S. Chatterjee and A. Pandey
Coronary artery disease continues to be an important
cause of mortality and morbidity. Sirolimus and paclitaxel
eluting stents have become an important treatment for patients
undergoing revascularization from coronary blockages. These
drug eluting stents have enjoyed great success initially in
preventing recurrences of adverse cardiac events and decreasing
the incidences of repeat revascularizations. However, adverse
effects, such as thrombosis, emanating from the use of these
drug eluting stents has recently come to focus. Hence a better
understanding of the mechanism of action of these drugs in
preventing restenosis is important for the long term success
and potential betterment of drug eluting stent technology.
Herein we review and discuss the pacpathophysiology of restenosis,
the basic mechanism of action of sirolimus andlitaxel eluting
stents and their limitations so as to create a scope for more
efficient and novel drug eluting stents in the future.
[Back to top]
Using Bioinformatics Techniques for Gene Identification
in Drug Discovery and Development
Y.-P. Phoebe Chen and F. Chen
As more and more evidence has become available, the link
between gene and emergent disease has been made including
cancer, heart disease and parkinsonism. Analyzing the diseases
and designing drugs with respect to the gene and protein level
obviously help to find the underlying causes of the diseases,
and to improve their rate of cure. The development of modern
molecular biology, biochemistry, data collection and analysis
techniques provides the scientists with a large amount of
gene data. To draw a link between genes and their relation
to disease outcomes and drug discovery is a big challenge:
How to analyze large datasets and extract useful knowledge?
Combining bioinformatics with drug discovery is a promising
method to tackle this issue. Most techniques of bioinformatics
are used in the first two phases of drug discovery to extract
interesting information and find important genes and/or proteins
for speeding the process of drug discovery, enhancing the
accuracy of analysis and reducing the cost. Gene identification
is a very fundamental and important technique among them.
In this paper, we have reviewed gene identification algorithms
and discussed their usage, relationships and challenges in
drug discovery and development.
[Back to top]
Predicting the Volume of Distribution of Drugs in
Humans
X. Sui, J. Sun, X. Wu, H. Li, J. Liu and Z. He
Recent studies have shown that many promising new drug
candidates were abandoned due to poor pharmacokinetic properties
(PKs). Therefore, it is important to predict the PKs of compounds
during the early stages of drug development. The volume of
distribution (VD) is one of the most important PK parameters.
When considered along with systemic clearance, the VD determines
the biological half-life, which is used for designing suitable
dosage regimens and rational formulations. At present, the
methods used to predict VD include (i) the extrapolation of
animal data, (ii) physiologically based pharmacokinetic (PBPK)
modeling and (iii) in silico approaches that employ quantitative
structure – pharmacokinetic relationships (QSPR). In
this article, the latest progress in the field of VD prediction
is summarized in terms of the above three areas, respectively,
and these approaches are expected to be valuable for screening
new drugs during the early stages of drug discovery and development.
|
