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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 9, Number 2, February 2008
Contents
Structure, Function and Polymorphism of Human Cytosolic
Sulfotransferases Pp. 99-105
J. Lindsay, L.-L. Wang, Y. Li and S.-F. Zhou
[Abstract]
Placental Drug Disposition and Its Clinical Implications
Pp. 106-121
N. Weier, S.-M. He, X.-T. Li, L.-L. Wang and S.-F. Zhou
[Abstract]
Modulation of Cardiac and Hepatic Cytochrome
P450 Enzymes during Heart Failure Pp. 122-128
B.N.M. Zordoky and A.O.S. El-Kadi
[Abstract]
Xenobiotic-Induced Transcriptional Regulation
of Xenobiotic Metabolizing Enzymes of the Cytochrome P450
Superfamily in Human Extrahepatic Tissues Pp. 129-143
P. Pavek and Z. Dvorak
[Abstract]
Lack of Interaction of the NMDA Receptor Antagonists
Dextromethorphan and Dextrorphan with P-Glycoprotein
Pp. 144-151
M. Kanaan, Y. Daali, P. Dayer and J. Desmeules
[Abstract]
Profiling Drug Membrane Permeability and Activity
Via Biopartitioning Chromatography Pp. 152-166
J. Sun, X. Wu, R. Lu, J. Liu,Y. Wang and Z. He
[Abstract]
Genuine Functions of P-Glycoprotein (ABCB1) Pp.
167-174
T. Mizutani, M. Masuda, E. Nakai, K. Furumiya, H. Togawa,
Y. Nakamura, Y. Kawai, K. Nakahira, S. Shinkai and K. Takahashi
[Abstract]
Cyclic Metabolites: Chemical and Biological Considerations
Pp. 175-188
J.C.L. Erve
[Abstract]
Abstracts
[Back to top]
Structure, Function and Polymorphism of Human Cytosolic Sulfotransferases
J. Lindsay, L.-L. Wang, Y. Li and S.-F. Zhou
The sulfotransferase (SULTs) catalyzes the sulfonation
of a multitude of xenobiotics, hormones and neurotransmitters.
This review has summarised the SULT family in detail, the
structure of the twelve known enzymes, in their four known
groups (SULT1, SULT2, SULT4, and SULT6) and the substrates
for each respective SULT. Hepatic sulfonation is a common
phase II metabolic mechanism for increasing molecular hydrophilicity
in preparation for biliary excretion or efflux across the
hepatic basolateral membrane for subsequent renal clearance.
To date, a total of 13 human cytosolic SULT genes
have been identified which spread across four families; SULT1,
SULT2, SULT4, and SULT6. The established
structures of SULTs provide evidence for both enzyme/substrate
and enzyme/cofactor binary complexes, consistent with a random
bi-bi mechanism and ruling out an ordered mechanism in which
binding of substrate requires binding of cofactor (or vice
versa). Members of the SULT1 family have demonstrated
the ability to sulfonate simple (small planar) phenols including
estradiol, thyroid hormones, environmental xenobiotics and
drugs. The SULT2 family members catalyze sulfonation of hydroxyl
groups of steroids, such as androsterone, allopregnanolone,
and dehydroepiandrosterone. As yet, no known substrate or
function has been identified for the SULT4 family, and the
SULT6B1 gene, expressed in the testis of primates,
has neither the protein nor its enzymatic activity characterized.
The extent of nucleotide variation found in members of the
SULT gene family is similar to that observed for
other groups of human genes. Substrate inhibition was observed
for most substrates with a trend in maximum velocity (Vmax)
of *1>*3>*2. There does appear
to be an inter-ethnic/inter-racial difference in the incidence
of the various SULT1A1 alleles also. There is mounting
evidence to suggest that further research and understanding
in the area of phase II metabolism and the SULT enzyme will
have a great benefit in a clinical setting. Already research
in the field is finding links with cancer and sulfonation-related
disease, promising to deliver great advances in clinical practice
in the future.
[Back to top]
Placental Drug Disposition and Its Clinical Implications
N. Weier, S.-M. He, X.-T. Li, L.-L. Wang and S.-F. Zhou
The placenta is a unique organ that is essential to a
healthy and normal pregnancy. A number of phase I and II metabolizing
enzymes are expressed at moderate levels in the placenta,
and have been proven to have the ability to metabolize certain
xenobiotics. Depending on the substrate, this metabolic action
may have significant clinical implications on how it affects
the fetus. A wide variety of transporters including P-glycoprotein,
breast cancer resistance protein, and multidrug resistance
associated proteins have also been discovered in the placenta,
and while most are found to have mainly physiological substrates,
there are a number of xenobiotics which are also able to gain
access to the fetus through transport across the placenta.
Depending on the xenobiotics and its intended action, drug
transport across the placenta may be desired, acceptable or
undesirable. Medications administered to the mother but designed
to work on the fetus are now being used increasingly, and
demonstrates an important clinical implication in which drug
transport across the placenta is desirable. However, medications
designed to treat the mother but are also able to cross the
placenta carry potential risks to damage the developing fetus,
and it is therefore essential that the effects of different
drugs on the fetus are known before they are administered
during pregnancy. There is still much unknown about drug transport
and drug metabolism in the placenta, and it is vital that
in the future further research is done to discover the clinical
implications of these activities in the placenta. This research
is often complicated by the fact that it is unethical to run
studies in pregnant women, and so research is often carried
out in pregnant animals. These results are not always accurate,
however, as the human’s placental structure is different
from the placenta in other animals. Drug metabolism and drug
transport across the placenta should continue to be researched,
and guidelines need to be developed to ensure that any medications
used during pregnancy are safe to both the mother and the
fetus, and that successful treatment of the medical condition
is carried out.
[Back to top]
Modulation of Cardiac and Hepatic Cytochrome P450 Enzymes
during Heart Failure
B.N.M. Zordoky and A.O.S. El-Kadi
Heart failure is a very serious cardiovascular disease
that affects more than five million people in North America.
The role of cytochrome P450 (CYP) in cardiovascular health
and disease is well established. Many CYP enzymes have been
identified in the heart and their levels have been reported
to be altered during cardiac hypertrophy and heart failure.
There is a great deal of discrepancy between various reports
on CYP alterations during heart failure, likely due to differences
in disease severity, species in question and other underlying
conditions. In general, however, cardiac CYP1B and CYP2A,
CYP2B, CYP2E, CYP2J, CYP4A and CYP11 mRNA levels and related
enzyme activities are usually increased. Moreover, there is
a strong correlation between CYP-mediated endogenous metabolites
and the pathogenesis of cardiac hypertrophy and heart failure.
Some of these metabolites confer cardioprotective effect such
as estradiol, dehydroepiandrosterone, epoxyeicosatrienoic
acids, and prostaglandin I2;
whereas, other metabolites may be harmful to the heart such
as androgens, aldosterone, hydroxyeicosatetraenoic acids,
and thromboxane A2. On the
other hand, heart failure plays an important role in the down-regulation
of hepatic CYP involved in drug metabolism through several
mechanisms which include hepatocellular damage, hypoxia, elevated
levels of pro-inflammatory cytokines, and increased production
of heme oxygenase-1. Therefore, more research is needed to
elucidate the mechanisms by which CYP affect the development
and/or progression of heart failure and also the mechanism
by which heart failure alters cardiac and hepatic CYP enzymes.
[Back to top]
Xenobiotic-Induced Transcriptional Regulation of Xenobiotic
Metabolizing Enzymes of the Cytochrome P450 Superfamily in
Human Extrahepatic Tissues
P. Pavek and Z. Dvorak
Numerous members of the cytochrome P450 (CYP) superfamily
are induced after exposure to a variety of xenobiotics in
human liver. We have gained considerable mechanistic insights
into these processes in hepatocytes and multiple ligand-activated
transcription factors have been identified over the past two
decades. Families CYP1, CYP2 and CYP3 involved in xenobiotic
metabolism are also expressed in a range of extrahepatic tissues
(e.g. intestine, brain, kidney, placenta, lung, adrenal gland,
pancreas, skin, mammary gland, uterus, ovary, testes and prostate).
Since the expression of the majority of the isoforms appears
to be very low in the extrahepatic tissues in comparison with
predominant expression in adult liver, the role of the enzymes
in overall biotransformation and total body clearance is minor.
However, basal expression and up-regulation of extrahepatic
CYP enzymes can significantly affect local disposition of
xenobiotics or endogenous compounds in peripheral tissues
and thus modify their pharmacological/toxicological effects
or affect absorption of xenobiotics into systemic circulation.
The goal of this review is to critically examine our current
understanding of molecular mechanisms involved in induction
of xenobiotic metabolizing CYP genes of human families CYP1,
CYP2 and CYP3 by exogenous chemicals in extrahepatic tissues.
We concentrate on organs such as the intestine, kidney, lung,
placenta and skin, which are involved in drug distribution
and clearance or are in direct contact with environmental
xenobiotics. We also discuss single nucleotide polymorphisms
(SNPs) of key CYPs, which at the level of transcription affect
expression of the genes in the extrahepatic tissues or are
associated with some pathophysiological stages or disorders
in the organs.
[Back to top]
Lack of Interaction of the NMDA Receptor Antagonists Dextromethorphan
and Dextrorphan with P-Glycoprotein
M. Kanaan, Y. Daali, P. Dayer and J. Desmeules
The anti-N-methyl-D-aspartate (NMDA) effect of dextromethorphan
(DEM) seems to be mainly related to the unchanged drug rather
than to its more potent metabolite dextrorphan (DOR). The
aim of our study was to assess the involvement of P-glycoprotein
(P-gp) and pH conditions in the transmembranal transport of
these two NMDA antagonists, using a human in vitro
Caco-2 cell monolayer model. Transmission electron microscopy,
transepithelial electrical resistance, [3H]
-mannitol permeability, Western blot analysis and the bidirectional
transport of the positive controls, rhodamine and digoxine
were used to confirm model’s integrity and validity.
The bidirectional transport of DEM and DOR (1 to 100μM)
across the monolayers was investigated in the presence and
absence of the P-gp inhibitor cyclosporine A (10μM)
at two pH conditions (pH 6.8/7.7-pH 7.4/7.4) and assessed
with the specific and more potent P-gp inhibitor GF120918
(4μM).
Analytical quantification was achieved using high performance
liquid chromatography. At a pH gradient, DEM and DOR were
subject to a significant active efflux transport (Papp(B-A)
> 2-3x Papp(A-B); p<0.01). However, neither the influx
nor the efflux was affected by P-gp inhibitors. At physiological
pH, we observed no more efflux of the drugs and no influence
of the inhibitors.
In conclusion, dextromethorphan and dextrorphan are not P-gp
substrates. However, pH-mediated efflux mechanisms seem to
be involved in limiting DEM gastrointestinal absorption. The
preferential anti-NMDA central effect of DEM appears to be
P-gp independent.
[Back to top]
Profiling Drug Membrane Permeability and Activity Via Biopartitioning
Chromatography
J. Sun, X. Wu, R. Lu, J. Liu,Y. Wang and Z. He
Drug in vivo pharmacokinetic performances in
nature consist of sequential membrane transporting processes
and are based on the entry into and exit of drugs from cell,
even for metabolism process requiring parent drugs delivered
into and metabolites effluxed from the metabolizing cells.
Efficient and reliable high throughput screen of membrane
permeability properties as early as possible in drug discovery
and development program is accordingly desirable.
Biopartitioning chromatography (BPC) introduces biomembrane-mimetic
structures (such as liposome, phospholipid monolayer, micelle,
microemulsion, vesicle and bicelle, etc) into chromatographic
system, i.e. liquid system or capillary electrophoresis, and
thereby emulates drug-membrane interactions difficult to study
in the liquid state by well reproducible, rapid, sensitive
and adequately designed chromatographic technique. And recently
BPC has been becoming a high-throughput screening platform
for drug membrane permeability and biological activity. The
theoretical basis, classification and application of BPC were
summarized based on the latest advances and our recent works.
The development potential and perspectives of this field were
also discussed.
[Back to top]
Genuine Functions of P-Glycoprotein (ABCB1)
T. Mizutani, M. Masuda, E. Nakai, K. Furumiya, H. Togawa,
Y. Nakamura, Y. Kawai, K. Nakahira, S. Shinkai and K. Takahashi
P-glycoprotein (P-gp, ABCB1, MDR1) was recognized as
a drug-exporting protein from cancer cells three decade ago.
Apart from the multidrug transporter side effects of P-gp,
normal physiological functions of P-gp have been reported.
P-gp could be responsible for translocating platelet-activating
factor (PAF) across the plasma membrane and PAF inhibited
drug transport mediated by P-gp in cancer cells. P-gp regulated
the translocation of sphingomyelin (SM) and GlcCer, and short
chain C6-NBD-GlcCer was found
in the apical medium of P-gp cells exclusively and not in
the basolateral membrane. SM plays an important role in the
esterification of cholesterol. High expression of P-gp prevents
stem-cell differentiation, leading to the proliferation and
amplification of this cell repertoire, and functional P-gp
plays a fundamental role in regulating programmed cell death,
apoptosis. The transporter function of P-gp is therefore necessary
to protect cells from death. P-gp can translocate both C6-NBD-PC
and C6-NBD-PE across the
apical membrane. This PC translocation was also confirmed
with [3 H]choline radioactivity.
Progesterone is not transported by P-gp, but blocks P-gp-mediated
efflux of other drugs and P-gp can mediate the transport of
a variety of steroids. Cells transfected with human P-gp esterified
more cholesterol. P-gp might also be involved in the transport
of cytokines, particularly IL-1β,
IL-2, IL-4 and IFNγ,
out of activated normal lymphocytes into the surrounding medium.
P-gp expression is also associated with a volume-activated
chloride channel, thus P-gp is bifunctional with both transport
and channel regulators. We also present information about
P-gp polymorphism and new structural concepts, "gate"
and "twist", of the P-gp structure.
[Back to top]
Cyclic Metabolites: Chemical and Biological Considerations
J.C.L. Erve
Metabolism of xenobiotics can sometimes generate cyclic
metabolites. Such metabolites are usually the result of intramolecular
reactions occurring within a primary or secondary metabolite
and this chemistry may lead to unexpected structures. Intramolecular
chemistry is often driven by nucleophilic groups reacting
with electrophilic atoms, often carbon, although radical processes
also occur. Conjugation of xenobiotics or their metabolites
with endogenous thiols, such as glutathione or cysteine, introduce
a reactive amino group that can lead to the formation of cyclic
structures. Less common than chemically driven cyclizations
are enzymatically mediated ring-closures, although this may
reflect our incomplete recognition of enzymatic involvement
in this step of cyclic metabolite formation. While some cyclic
metabolites are biologically inactive, others are biologically
active. Thus, a cyclic metabolite may display desirable pharmacology,
or, contribute to toxicology. When a cyclic metabolite is
identified, it is important to consider the possibility that
it is an artifact, i.e. metabonate, that was formed during
processing of the sample, for example, through degradation
or by chemical reactions with other components present in
the matrix. From a medicinal chemistry perspective, a cyclic
metabolite with a different chemical scaffold from the parent
structure may lead to a new series of structurally novel,
biologically active molecules with the same, or different,
pharmacology from the parent. This review will cover a selection
of cyclic metabolites from a mechanistic point of view, and
when possible, discuss their biological relevance.
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