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Current Enzyme Inhibition
ISSN: 1573-4080
Current Enzyme Inhibition
Volume 3, Number 3, August 2007
Contents
Paraoxonase-1 (PON1) as a Predictor of Biochemical
Outcomes in Farmers Pp. 175-182
Antonio F. Hernández, Olga López, Gloria
Pena, José L. Serrano, Tesifón Parrón,
Lourdes Rodrigo, Fernando Gil and Antonio Pla
[Abstract]
Vascular Endothelial Growth Factor (VEGF) in
Pleural Effusions Pp. 183-188
Theodoros S. Kiropoulos, Zoe Daniil, Konstantinos I. Gourgoulianis
and Epaminondas Zakynthinos
[Abstract]
Regulation of Oxidative Phosphorylation by Inhibition
of its Enzyme Complexes via Reversible Phosphorylation
Pp. 189-206
Sebastian Vogt, Annika Rhiel, Verena Koch and Bernhard
Kadenbach
[Abstract]
Histone Deacetylase Inhibitors: Novel Immunomodulators
Pp. 207-215
Yaping Sun and Pavan Reddy
[Abstract]
In Vivo Assessment of Cytochrome
P450 3A4 and P-Glycoprotein Activity: Impact on Clinical Practice
Pp. 217-241
Wim Lemahieu and Bart Maes
[Abstract]
Ruthenium Complex as Enzyme Modulator: Modulation
of Lactate Dehydrogenase by a Novel Ruthenium(II) Complex
Containing 4 Carboxy N-Ethylbenzamide as a Ligand
Pp. 243-253
Surendra K. Trigun, Raj K. Koiri, Lallan Mishra, Santosh
K. Dubey, Santosh Singh and Pankaj Pandey
[Abstract]
Abstracts
[Back to top]
Paraoxonase-1 (PON1) as a Predictor of Biochemical
Outcomes in Farmers
Antonio F. Hernández, Olga López, Gloria
Pena, José L. Serrano, Tesifón Parrón,
Lourdes Rodrigo, Fernando Gil and Antonio Pla
Initially characterized for its ability to hydrolyze
organophosphorus (OP) compounds, Paraoxonase-1 (PON1) has
been reported to play an important role in modulating the
toxicity of some of these agents, which are “in
vitro” substrates for this enzyme. The PON1 polymorphism
at position 192 confers different enzyme levels and catalytic
activity in a substrate-dependent manner, which has been related
to the differential sensitivity of individuals to the toxic
effects of OPs, supporting a role for the enzyme as a susceptibility
biomarker. Several epidemiologic studies have examined the
involvement of PON1 in xenobiotic susceptibility in different
scenarios, including occupational exposure to pesticides.
The major results of our studies performed in plastic greenhouses
workers from Southeast Spain are presented herein. Briefly,
PON1 is not only an individual marker of susceptibility, but
also a biological indicator of exposure to pesticides, since
workers spraying these agents, mainly OPs, showed decreased
enzyme levels. On the other hand, carriers of the PON1 192R
allele had lower levels of erythrocyte cholinesterase, a lower
risk of presenting pesticide-related symptomatology, and less
risk of reporting a previous episode of pesticide poisoning.
Regarding enzymes involved in oxidative stress, carriers of
the PON1 R allele had higher glutathione reductase and lower
catalase activities. Intriguingly, PON1 R allele was found
to be an independent predictor of higher aspartate aminotransferase
and lower amino-oxidase and creatine kinase activities in
serum. These findings deserve further attention as they highlight
the important role of individual biomarkers of susceptibility
on pesticide-induced biochemical changes in target organs
that may precede the appearance of clinical changes.
[Back to top]
Vascular Endothelial Growth Factor (VEGF) in
Pleural Effusions
Theodoros S. Kiropoulos, Zoe Daniil, Konstantinos I. Gourgoulianis
and Epaminondas Zakynthinos
Pleural effusion is a common clinical problem in everyday
clinical practice. Vascular endothelial growth factor (VEGF)
is a 34-45 kDa homodimeric glycoprotein, which is a potent
mediator of angiogenesis and vascular permeability. VEGF is
present in significant quantities in pleural effusions of
different origins, and its levels are consistently higher
in exudates than in transudates. There is compelling experimental
evidence demonstrating that VEGF is a crucial mediator in
fluid formation. In the pleural space mesothelial cells are
likely the principal source of fluid VEGF. It is also produced
by most malignant cell types and inflammatory cells including
lymphocytes, eosinophils, macrophages, and neutrophls. VEGF
production can be stimulated by various cytokines, among which
transforming growth factor beta (TGF-β)
appears to be the most potent and consistent. Hypoxia and
ischemia are the most established physical stimulators of
VEGF. Promising results are rapidly accumulating on the use
of VEGF inhibition in preventing pleural fluid accumulation;
clinical trials are underway using VEGF antagonists in the
management of malignant pleural effusions. The main focus
of this review is to evaluate the role of VEGF in the pathogenesis
and differential diagnosis of pleural effusions as well as
the therapeutic implications of VEGF in control of effusions
formation.
[Back to top]
Regulation of Oxidative Phosphorylation by Inhibition
of its Enzyme Complexes via Reversible Phosphorylation
Sebastian Vogt, Annika Rhiel, Verena Koch and Bernhard
Kadenbach
Recent experimental results indicate that oxidative phosphorylation
in mitochondria is not only regulated by “respiratory
control”, i.e., inhibition of respiration at low ATP
utilization via the electrochemical proton gradient across
the inner mitochondrial membrane, but in addition by reversible
phosphorylation of respiratory chain complexes and of ATP
synthase. Thus the formation of ATP and the generation of
heat by mitochondria is also controlled by second messenger-mediated
signal transduction mechanisms. The second messengers include
cAMP, calcium, and ROS leading to activation of mitochondrial
protein kinases and phosphatases. Some protein kinases (e.g.,
PKB = Akt, PKC) have been demonstrated to be translocated
into mitochondria after activation (phosphorylation) outside
of mitochondria. Subunit phosphorylation has been described
for complexes I (NADH dehydrogenase), II (succinate dehydrogenase),
III (cytochrome c reductase), IV (cytochrome c oxidase) and
V (ATP synthase). Of particular interest is the phosphorylation
of complex IV leading to an allosteric ATP-inhibition of cytochrome
c oxidase, representing a second mechanism of respiratory
control.
[Back to top]
Histone Deacetylase Inhibitors: Novel Immunomodulators
Yaping Sun and Pavan Reddy
Chromatin remodeling by acetylation/deacetylation of histones
plays an important role in the regulation of gene expression.
Acetylation of histones is regulated by two classes of enzymes:
histone acetyltransferases (HATs) and histone deacetylases
(HDACs). Several HDAC inhibitors, belonging to different structural
classes, cause reversible inhibition of HDAC enzymes. They
cause hyperacetylation of histones and have shown efficacy
in experimental systems as anti-tumor agents. Phase I /II
clinical trials with some of these agents have demonstrated
that they are relatively well-tolerated and have anti-tumor
activity in heavily pre-treated patients with advanced solid
and hematological tumors. The effects of HDAC inhibition are
believed to be caused, in part, by accumulation of acetylated
histones, although the exact mechanism of gene repression
or activation is not well understood. Recent data from our
and several other laboratories demonstrate that HDAC inhibitors
have potent immuno-modulatory activities that have previously
been largely unrecognized. Importantly, inhibition of HDAC
enzymes by a far less concentration than required for anti-tumor
effects is sufficient for induction of immuno-modulation by
these compounds. This review addresses the issue of HDAC inhibitors
and their effects on immuno-modulation on both in vitro
and in vivo models of inflammation, autoimmunity
and transplantation. The likely molecular and biochemical
underpinnings of these novel effects will be reviewed and
the potential clinical benefits will also be briefly discussed.
[Back to top]
In Vivo Assessment of Cytochrome
P450 3A4 and P-Glycoprotein Activity: Impact on Clinical Practice
Wim Lemahieu and Bart Maes
Both bioavailability and clearance of most drugs for human
use are strongly determined by hepatic and intestinal metabolism
and transport. This is especially relevant for so-called narrow
therapeutic index drugs, necessitating the use of therapeutic
drug monitoring in many clinical settings. Cytochrome P450
3A4 (CYP3A4) is a key enzyme involved in over half of all
phase I drug metabolism reactions and is abundantly present
in the endoplasmic reticulum of both hepatocytes and enterocytes.
P-glycoprotein (PGP), also known as MDR1 or ABCB1, is one
of the first discovered and still most important active drug
efflux pumps. Its localization on the apical cell membrane
of hepatocytes zooming bile canaliculi and its relative distribution
along the intestinal tract (PGP is mainly situated in the
distal gastrointestinal tract, as opposed to CYP3A4, which
is most prevalent in the proximal part) strongly suggests
an interplay between these two proteins, optimizing the organisms
defence against xenobiotics. To date, the main part of all
research on CYP3A4 and PGP has been conducted in vitro
and mostly using systems expressing either CYP3A4 or
PGP. Since it has proven difficult to ‘scale up’
from in vitro results to clinically relevant phenomena
such as potentially life threatening drug-drug interactions,
several attempts have been made to bridge this ‘gap’
by assessing CYP3A4 and PGP activity in vivo. This
review will focus on currently available methods for CYP3A4/PGP
measurement in vivo and its impact on clinical practice,
particularly in the field of clinical immunosuppression.
[Back to top]
Ruthenium Complex as Enzyme Modulator: Modulation
of Lactate Dehydrogenase by a Novel Ruthenium(II) Complex
Containing 4 Carboxy N-Ethylbenzamide as a Ligand
Surendra K. Trigun, Raj K. Koiri, Lallan Mishra, Santosh
K. Dubey, Santosh Singh and Pankaj Pandey
Ruthenium complex-protein interaction, particularly with respect
to modulation of the enzymes associated to tumor development,
is an evolving concept in understanding the mechanism of action
of these complexes as anticancer agent. Lactate dehydrogenase
(LDH; EC: 1.1.1.27) is critically implicated in maintaining
tumor growth via ‘Warburg effect’ in
cancerous cells. This article presents current status of Ru-complexes
as enzyme inhibitors in general and a state of art on a novel
ruthenium(II) complex containing 4-Carboxy-N-ethylbenzamide
as an inhibitor of LDH. The 4-carboxy-N-ethylbenzamide (CNEB)
was synthesized and characterized by single crystal X-ray
measurement and complexed with cis-Ru(bpy)2Cl2.2H2O
(bpy=2,2’bipyridine) resulting into synthesis of a [Ru(CNEB)2(bpy)2]
2PF6.0.5 NH4PF6]
complex, Ru(II)-CNEB. The complex showed appreciable cytotoxicity
on Dalton’s lymphoma cells and a significant Ru(II)-CNEB-LDH
interaction (Kc = 1.525 x 105
M-1).
The later was further confirmed from luminescence quenching
and gel retardation assays. The complex also caused a significant
decline in the activities of purified LDH and LDH from mice
liver extract. The complex was further characterized as a
non-competitive inhibitor of LDH (Ki
= 0.032 mM). Ru(II)-CNEB complex perfused mice liver also
showed a significant decline in LDH activity coinciding with
similar changes in the intensity of LDH bands on polyacrylamide
gel electrophoresis. Thus, Ru(II)-CNEB complex, as a non-competitive
inhibitor of LDH, seems to be a candidate for potential therapeutic
applications.
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