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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 7, Number 6, August 2006
Contents
Pharmacokinetics of Recombinant Human Endostatin
in Rats Pp. 565-576
X.-X. Yang, Z.-P. Hu, E. Chan, W. Duan and S. Zhou
[Abstract]
Induction of Propranolol Metabolism by Ginkgo
biloba Extract EGb 761 in Rats Pp. 577-587
L.-Z. Zhao, M. Huang, J. Chen, P.L.R. Ee, E. Chan, W.
Duan, Y. Y. Guan, Y.-H. Hong, X. Chen and S. Zhou
[Abstract]
Investigating Human P450s Involved in Drug Metabolism
via Homology with High-Resolution P450 Crystal Structures
of the CYP2C Subfamily Pp. 589-598
D.F.V. Lewis, Y. Ito and P.S. Goldfarb
[Abstract]
Antitumoral Activity of Interferon-γ
Involved in Impaired Immune Function in Cancer Patients
Pp. 599-612
G. Brandacher, C. Winkler, K. Schroecksnadel, R. Margreiter
and D. Fuchs
[Abstract]
Relevance of the Deletion Polymorphisms of the
Glutathione S-Transferases GSTT1 and GSTM1
in Pharmacology and Toxicology Pp. 613-628
H.M. Bolt and R. Thier
[Abstract]
Molecular Mechanisms Underlying the Dedifferentiation
Process of Isolated Hepatocytes and Their Cultures
Pp. 629-660
G. Elaut, T. Henkens, P. Papeleu, S. Snykers, M. Vinken,
T. Vanhaecke and V. Rogiers
[Abstract]
Modulation of Metabolic Enzymes by Dietary Phytochemicals:
A Review of Mechanisms Underlying Beneficial Versus Unfavorable
Effects Pp. 661-675
S. Mandlekar, J.-L. Hong and A.-N.T. Kong
[Abstract]
Thalidomide Metabolism and Hydrolysis: Mechanisms
and Implications Pp. 677-685
E.R. Lepper, N.F. Smith, M.C. Cox, C.D. Scripture and
W.D. Figg
[Abstract]
Abstracts
[Back to top]
Pharmacokinetics of Recombinant Human Endostatin in
Rats
X.-X. Yang, Z.-P. Hu, E. Chan, W. Duan and S. Zhou
The pharmacokinetics of recombinant human endostatin (rh-Endo)
has not been established in the rat, although this species
of animal is commonly used in the pharmacological studies
of rh-Endo. This study aimed to investigate the pharmacokinetics,
tissue distribution, and excretion of rh-Endo in rats. 125I-radiolabeled
rh-Endo was administered to healthy rats by intravenous (i.v)
bolus injection at 1.5, 4.5 and 13.5 mg/kg. The maximum plasma
concentration (Cmax)
and area under the plasma concentration versus time curve
(AUC) of rh-Endo increased proportionally with the increase
of the dosage. There were no significant differences in total
body clearance (CL) and elimination half-life (t½β)
of rh-Endo among the three dosages used. A 93.5% and 2.2%
of the radioactivity was recovered in the urine and feces,
respectively, in bile-duct intact rats; whereas only 0.1%
of the total radioactivity was excreted into the bile in bile-duct
cannulated rats. rh-Endo was rapidly and widely distributed
in the liver, kidneys, spleen and lungs. Furthermore, a significant
allometric relationship between CL, but not volume of distribution
(Vd)
and t½β
of rh-Endo, and the body weight was observed across mouse,
rat and monkey, with the predicted values in humans significantly
lower than those observed in cancer patients. rh-Endo exhibited
a linear pharmacokinetics in rats and it is mainly excreted
through the urine.
[Back to top]
Induction of Propranolol Metabolism by Ginkgo
biloba Extract EGb 761 in Rats
L.-Z. Zhao, M. Huang, J. Chen, P.L.R. Ee, E. Chan, W.
Duan, Y. Y. Guan, Y.-H. Hong, X. Chen and S. Zhou
Ginkgo biloba is one of the most popular herbal medicines
in the world, due to its purported pharmacological effects,
including memory-enhancing, cognition-improving, and antiplatelet
effects. When used in the elderly, Ginkgo has a high potential
for interactions with cardiovascular drugs. This study aimed
to investigate the effects of the standard Ginkgo biloba
extract (EGB 761) treatment on the pharmacokinetics of propranolol
and its metabolism to form N-desisopropylpropranolol
(NDP) in rats. We also examined the activity and expression
of cytochrome P450 (CYP) 1A and other CYPs in rats treated
with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single
oral dose of propranolol (10 mg/kg) was administered on day
11 and the concentrations of both propranolol and NDP were
determined using validated liquid chromatography-mass spectrometry
(LC-MS) methods. The levels of mRNA and protein of various
CYPs were determined by RT-PCR and Western blotting analysis,
respectively. Pretreatment of EGb 761 at 100 mg/kg, but not
10 mg/kg, for 10 days significantly reduced the area under
the plasma concentration-time curve (AUC) and maximum plasma
concentration (Cmax)
of propranolol, whereas those values of NDP were significantly
increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene
expression in the rat liver were significantly increased in
a dose-dependent manner by pre-treatment with EGb 761. The
ex-vivo formation of NDP in liver microsomes from
rats pretreated with EGb 761 was markedly enhanced. The formation
of NDP from propranolol in liver microsomes was significantly
inhibited by α-naphthoflavone
(ANF, a selective CYP1A2 inhibitor), but not by quinidine
(a CYP2D inhibitor). These results indicated that EGb 761
pretreatment decreased the plasma concentrations of propranolol
by accelerated conversion of parental drug to NDP due to induction
of CYP1A2. EGb 761 pretreatment also significantly induced
CYP2B1/2 and CYP3A1, suggesting potential interactions with
substrate drugs for these two enzymes. Further study is needed
to explore the potential for gingko-drug interactions and
the clinical impact.
[Back to top]
Investigating Human P450s Involved in Drug Metabolism
via Homology with High-Resolution P450 Crystal Structures
of the CYP2C Subfamily
D.F.V. Lewis, Y. Ito and P.S. Goldfarb
The important role of high-resolution crystal structures of
cytochrome P450 (CYP) enzymes for the generation of P450 models
by homology is discussed. The main focus is on human P450
enzymes involved in drug metabolism, where the role of homology
modelling has been emphasized in the recent literature. Report
of the first human P450 crystal structure has provided an
opportunity for comparison between those modelled from other
crystallographic templates, and the recent substrate-bound
rabbit CYP2C5 structure exemplifies the relevance of high-resolution
template structures to generating 3-D models of P450s where
the homology is relatively high. In particular, the homology
models of human CYP1 and CYP2 family enzymes are presented,
where good agreement with experiment findings are apparent.
[Back to top]
Antitumoral Activity of Interferon-γ
Involved in Impaired Immune Function in Cancer Patients
G. Brandacher, C. Winkler, K. Schroecksnadel, R. Margreiter
and D. Fuchs
Insufficient immunosurveillance is an important aspect in
early tumorigenesis and in the pathogenesis of malignant disease.
In the later course of cancer, the development of immunodeficiency
is considered the major reason for disease progression and
death. Within the anti-tumoral host defense reaction, Th1-type
cytokine interferon-γ
(IFN-γ)
is of particular relevance. IFN-γ
stimulates several anti-proliferative and thus tumoricidal
biochemical pathways in macrophages and other cells and also
in tumor cell lines. These include inducible nitric oxide
synthase, indoleamine (2, 3)-dioxygenase, an enzyme degrading
the essential amino acid tryptophan, and the production of
reactive oxygen species and neopterin in human macrophages
and dendritic cells. Although the anti-proliferative strategy
of the immune system aims to inhibit the growth of malignant
cells, it can also affect T-cell response and thus contribute
to the development of immunodeficiency. Accelerated degradation
of tryptophan and increased production of neopterin were found
to parallel the course of malignant diseases. Moreover, a
higher degree of these metabolic changes characterizes poor
prognosis and is associated with the development of anemia,
weight loss and depressive mood in patients. Available data
suggest that immunodeficiency in cancer patients may develop
as a long-term side-effect of the antiproliferative and pro-apoptotic
mechanisms elicited within Th1-type immune response, and enhanced
production of pro-inflammatory cytokine IFN-γ
seems to be critically involved.
[Back to top]
Relevance of the Deletion Polymorphisms of the
Glutathione S-Transferases GSTT1 and GSTM1
in Pharmacology and Toxicology
H.M. Bolt and R. Thier
Although cytosolic glutathione S-transferase (GST)
enzymes occupy a key position in biological detoxification
processes, two of the most relevant human isoenzymes, GSTT1-1
and GSTM1-1, are genetically deleted (non-functional alleles
GSTT1*0 and GSTM1*0) in a high percentage of the human population,
with major ethnic differences. The structures of the GSTT
and GSTM gene areas explain the underlying genetic processes.
GSTT1-1 is highly conserved during evolution and plays a major
role in phase-II biotransformation of a number of drugs and
industrial chemicals, e.g. cytostatic drugs, hydrocarbons
and halogenated hydrocarbons. GSTM1-1 is particularly relevant
in the deactivation of carcinogenic intermediates of polycyclic
aromatic hydrocarbons. Several lines of evidence suggest that
hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of
reactive oxygen species that are likely to be involved in
cellular processes of inflammation, ageing and degenerative
diseases. There is cumulating evidence that combinations of
the GSTM1*0 state with other genetic traits affecting the
metabolism of carcinogens (CYP1A1, GSTP1) may predispose the
aero-digestive tract and lung, especially in smokers, to a
higher risk of cancer. The GSTM1*0 status appears also associated
with a modest increase in the risk of bladder cancer, consistent
with a GSTM1 interaction with carcinogenic tobacco smoke constituents.
Both human GST deletions, although largely counterbalanced
by overlapping substrate affinities within the GST superfamily,
have consequences when the organism comes into contact with
distinct man-made chemicals. This appears relevant in industrial
toxicology and in drug metabolism.
[Back
to top]
Molecular Mechanisms Underlying the Dedifferentiation
Process of Isolated Hepatocytes and Their Cultures
G. Elaut, T. Henkens, P. Papeleu, S. Snykers, M. Vinken,
T. Vanhaecke and V. Rogiers
Primary hepatocytes and their cultures are a simple but versatile,
well-controlled, and relatively easy to handle in vitro
system that is well-accepted for investigating xenobiotic
biotransformation, enzyme induction and inhibition, and (biotransformation-mediated)
hepatotoxicity. In addition, hepatocyte cultures have proven
to be valuable tools in the study of liver physiology, viral
hepatitis, and liver regeneration and are proposed as an alternative
to orthotopic liver transplantation. It has been observed,
however, that a number of liver-specific functions are progressively
lost with time when hepatocytes are isolated and cultivated.
These phenotypic changes are primarily the result of fundamental
changes in gene expression concomitant with a diminished transcription
of the relevant liver-specific genes, and can be interpreted
as a ‘dedifferentiation’ of the isolated hepatocytes.
Ischemia-reperfusion stress induced during the isolation process,
disruption of the normal tissue architecture, as well as an
adaptation to the in vitro environment are underlying
factors and will be extensively discussed. A detailed description
of the regulation of the hepatocyte phenotype in vivo
in the first section of this review will help to understand
the effect of these factors on hepatocyte gene expression.
Although different approaches, mainly mimicking the in
vivo hepatocyte environment, have been succesfully used
to prevent or slow down the dedifferentiation of primary hepatocytes
in monolayer culture, the ideal hepatocyte-based culture model,
characterized by a long-term expression of hepatocyte-specific
functions comparable to the in vivo level, does not
exist at the moment. Consequently, alternative strategies
should focus on the isolation procedure, during which dedifferentiation
is already initiated. In addition, identification of the conditions
needed for the full in vitro maturation of hepatic
progenitor cells to quiescent, functional hepatocyte-like
cells opens promising perspectives.
[Back to top]
Modulation of Metabolic Enzymes by Dietary Phytochemicals:
A Review of Mechanisms Underlying Beneficial Versus Unfavorable
Effects
S. Mandlekar, J.-L. Hong and A.-N.T. Kong
In this review, we extensively survey the literature documenting
the interaction of herbal components of the diet with metabolic
enzymes. These interactions are mediated by the phytochemicals
contained in herbs and can mechanistically occur at both transcriptional
or post-transcriptional level. At the transcriptional level,
dietary phytochemicals can cause induction of drug metabolizing
enzymes (DME’s: phase I and phase II) and transporters
via nuclear hormone receptors, including the pregnane
X receptor (PXR), the constitutive androstane receptor (CAR)
or the aryl hydrocarbon receptor (AHR), as well as non-hormonal
receptors, including the nuclear factor erythroid-derived
2 (NRF2) transcription factor. Herbs can also modulate the
activity of DME’s and transporters by competitive binding
to or inactivation of the protein. There are cases where herbal
constituents can undergo DME-mediated “bioactivation”
resulting in DNA adduct formation and toxicity. The consequences
of herb-DME interactions can be a) beneficial effects, such
as cancer prevention, b) undesirable effects, such as pharmacokinetic
interactions with co-administered drugs, c) harmful effects,
such as organ toxicity or carcinogenesis. The molecular, cellular,
and physiological mechanisms of herb-DME interactions will
be discussed with examples of in vitro, animal or
clinical studies of phytochemicals and in the context of human
health benefits or risks.
[Back to top]
Thalidomide Metabolism and Hydrolysis: Mechanisms
and Implications
E.R. Lepper, N.F. Smith, M.C. Cox, C.D. Scripture and
W.D. Figg
Despite its controversial past, thalidomide is currently under
investigation for the treatment of several disease types,
ranging from inflammatory conditions to cancer. The mechanism
of action of thalidomide is complex and not yet fully understood,
but there is some evidence to suggest that metabolism may
play a role. Consequently, there has been a considerable effort
to characterize the metabolism of thalidomide in recent years.
Thalidomide undergoes biotransformation by non-enzymatic hydrolysis
and enzyme-mediated hydroxylation to form a multitude of metabolites.
Metabolite identification and reaction phenotyping studies
have been performed and will be discussed in this review in
addition to interspecies differences in thalidomide metabolism.
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