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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 8, Number 6, August 2007
Contents
Metabolic Activation of Herbal and Dietary Constituents
and Its Clinical and Toxicological Implications: An Update
Pp. 526-553
S.-F. Zhou, C.C. Xue, X.-Q. Yu and G. Wang
[Abstract]
Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing
Anticancer Drugs for Personalized Cancer Chemotherapy
Pp. 554-562
K.-I. Fujita and Y. Sasaki
[Abstract]
Overlapping Ligand Specificity of P-Glycoprotein and
Serum α1
Acid Glycoprotein: Evidences and Potential Implications
Pp. 563-593
F. Zsila
[Abstract]
Control by Substrate of the Cytochrome P450-Dependent
Redox Machinery: Mechanistic Insights Pp. 594-611
P. Hlavica
[Abstract]
N-Dealkylation of Arylpiperazine Derivatives: Disposition
and Metabolism of the 1-Aryl-Piperazines Formed Pp.
612-622
S. Caccia
[Abstract]
Different Roles of Pummelo Furanocoumarin and Cytochrome
P450 3A5*3 Polymorphism in the Fate and Action of Felodipine
Pp. 623-630
L.-Q. Guo, Q.-Y. Chen, X. Wang, Y.-X. Liu, X.-M. Chu,
X.-M. Cao, J.-H. Li and Y. Yamazoe
[Abstract]
The Regulation of Liver Cytochrome P450 by the Brain
Dopaminergic System Pp. 631-638
J. Wójcikowski, K. Golembiowska and W.A. Daniel
[Abstract]
Different Inflammatory Biomarker Patterns in the Cerebro-Spinal
Fluid Following Heart Surgery and Major Non-Cardiac Operations
Pp. 639-642
H.J. Reis, A.L. Teixeira, J. Kálmán, G.
Bogáts, B. Babik, Z. Janka, M.M. Teixeira and A. Palotás
[Abstract]
Abstracts
[Back to top]
Metabolic Activation of Herbal and Dietary
Constituents and Its Clinical and Toxicological Implications:
An Update
S.-F. Zhou, C.C. Xue, X.-Q. Yu and G. Wang
In recent years, there has been a globally increasing application
of herbal medicines and dietary supplements to treat various
chronic diseases and to promote health. However, there are
increasing clinical reports on the organ toxicities associated
with consumption of herbal medicines. This review updates
the knowledge on metabolic activation of herbal components
and its clinical and toxicological implications. Like many
synthetic drugs undergoing metabolic activation to form reactive
metabolites which are often associated with drug toxicity,
it is recognized that some herbal components may also be converted
to toxic, or even mutagenetic and carcinogenic me-tabolites
by cytochrome P450s (CYPs) and less frequently by Phase II
conjugating enzymes. This is exemplified by aristolochic acids
(AAs) in Aristolochia spp, which undergo reduction
of the nitro group by hepatic CYP1A1/2 or peroxidases in extrahepatic
tissues to generate highly reactive cyclic nitrenium ions.
The latter can react with macromolecules (DNA and protein),
resulting in activation of H-ras oncogene and gene
mutation in renal cells and finally carcinogenesis of the
kidneys. Some naturally occurring flavonoids (e.g. quercetin)
and alkenylbenzenes (e.g. safrole, methyleugenol and estragole)
can undergo metabolic activation by sequential 1-hydroxylation
and sulfation, resulting in reactive intermediates capable
of forming DNA adducts and finally genotoxicity. Additional
examples are pulegone present in essential oils from many
mint species; and teucrin A, a diterpenoid found in germander
(Teuchrium chamaedrys) used as an adjuvant to slimming
dietary supplements but caused severe hepatotoxicity. Extensive
pulegone metabolism generated p-cresol that was a
glutathione depletory, whereas the furan ring of the diterpenoids
in germander was oxidized by CYP3A4 to reactive epoxide which
can inactivate hepatic CYP3A and epoxide hydrolase through
covalent binding. The hepatotoxic and carcinogenic species
of plant pyrrolizidine alkaloids (e.g. echimidine and jacobine),
namely pyrrole-type metabolites, are generated by hepatic
CYP2B6 and CYP3A4. Potential mechanisms underlying the hepatotoxicity
of kava have been related to intracellular glutathione depletion
and/or quinone formation. Some herbal constituents (e.g. capsaicin
from chili peppers, glabridin from licorice root, oleuropein
in olive oil, dially sulfone in garlic, and resveratrol found
in red wine) behave as mechanism-based inhibitors of various
CYPs. This may provide an explanation for some reported herb-drug
interactions. In addition, the inhibition of CYPs by herbal
constituents may decrease the formation of toxic metabolites
and thus inhibit carcinogenesis, as CYPs play an important
role in procarcinogen activation. Due to the wide use and
easy availability of herbal medicines, further research should
be conducted to ensure the safety and quality of herbal medicine.
[Back to top]
Pharmacogenomics in Drug-Metabolizing Enzymes Catalyzing
Anticancer Drugs for Personalized Cancer Chemotherapy
K.-I. Fujita and Y. Sasaki
Cancer chemotherapy is characterized by a broad range of efficacy
and toxicity among patients. Most anticancer drugs show wide
interindividual variability in pharmacokinetics and have narrow
therapeutic windows. Since drug metabolism is often an essential
determinant of interindividual variability in pharmacokinetics,
pharmacogenomic studies of drug-metabolizing enzymes are expected
to rationalize cancer chemotherapy in terms of patient, treatment,
and dosage selection.
Candidate gene approaches to pharmacogenomics are based on
existing knowledge in clinical pharmacology, used to select
the target(s) to be analyzed. So far, the candidate gene approach
has provided important clues for pharmacogenomic-based personalized
chemotherapy with 6-mercaptopurine (6-MP), solely metabolized
by thiopurine S-methyltransferase (TPMT), and irinotecan,
mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1).
Reduced activity of TPMT caused by polymorphisms in the TPMT
gene and decreased activity of UGT1A1 caused by UGT1A1*28
are related to severe toxic effects of 6-MP and irinotecan,
respectively. In response to these findings, the Food and
Drug Administration in the United States has supported clinical
pharmacogenetic testing by revising the package inserts for
these anticancer drugs.
The genome wide approach to pharmacogenomics has gradually
evolved with continued progress in genome sciences and technologies.
This approach can disclose previously unknown relations of
factors, as well as identify potential multigenetic associations.
The genome wide approach can also identify genes underlying
the phenotypic effects of anticancer drugs. This approach
may play a complemental role to the candidate gene approach
in the future of cancer pharmacogenomics.
This review describes recent progress in pharmacogenomics
in the field of cancer chemotherapy.
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Overlapping Ligand Specificity of P-Glycoprotein and
Serum α1
Acid Glycoprotein: Evidences and Potential Implications
F. Zsila
Plasma α1-acid
glycoprotein (AGP) is an important modulator of drug disposition,
since it binds and transports of a vast array of pharmaceutical
agents. The ABC transporter efflux pump, P-glycoprotein (P-gp),
also recognizes and binds a broad range of weakly basic and
uncharged xenobiotics. Its efflux activity plays a key role
in pharmacokinetics of drugs, and overexpression of P-gp in
malignant cells confers multidrug resistance (MDR) to anticancer
agents. Comparison of ligand specificities of AGP and P-gp
revealed high similarity showing that both proteins interact
with the same therapeutic classes of drugs (α/β-blockers,
anticancer agents, Ca2+ antagonists,
antipsychotics/neuroleptics, HIV protease inhibitors etc.)
as well as with additional endo- and exogenous compounds (steroids,
dyes, natural substances). A wealth of examples are presented
to show the potential use of drug-AGP binding data to predict
drug-P-gp interactions and vice versa. In addition, structural
and functional similarities between AGP and P-gp have been
highlighted. Based on these data, several proposals have been
made: 1) AGP and P-gp might act synergistically in protecting
cells from harmful xenobiotics; 2) An extensive shared list
of their ligands allows prediction of mutual binding interactions;
3) Interaction of drugs and drug candidates, both with AGP
and P-gp, should be considered to optimize pharmacotherapy
and to delineate the causes of drug-drug interactions; 4)
Structures of known AGP binders could be exploited in searching
for novel scaffolds of P-gp modulators to overcome cancer
MDR and efflux-mediated resistance in microorganisms and parasites;
5) Novel fluorescent probes for studying P-gp structure and
function can be pre-selected among AGP binder agents.
[Back to top]
Control by Substrate of the Cytochrome P450-Dependent
Redox Machinery: Mechanistic Insights
P. Hlavica
Based on initial studies with bacterial CYP101A1, a popular
concept emerged predicting that substrate-induced low-to-high
spin conversion of P450s is universally associated with shifts
of the midpoint potential to a more positive value to maximize
rates of electron transfer and metabolic turnover. However,
evaluation of the plethora of observations with pro- and eukaryotic
hemoproteins suggests a caveat as to generalization of this
principle. Thus, some P450s are inherently high-spin, so that
there is no need for a supportive substrate-triggered impulse
to electron flow. With other enzymes, high-spin content is
not consonant with reductive activity, and spin transition
as such is not essential to sustaining substrate oxidation.
Also, with certain proteins the low-spin conformer is reduced
as swift as the high-spin entity. Moreover, there is not regularly
a linear relationship between high-spin level and anodic shift
of the reduction potential. Similarly, in given cases turnover
may proceed despite insignificant or even lacking substrate-provoked
alterations in the redox behaviour. Thus, folding of the disparate
and sometimes conflicting data into a harmonized overall picture
is a lingering problem. Apart from direct perturbation of
the electrochemical properties, substrate docking may entail
changes in enzyme conformation such as to favour productive
complexation with redox partners or modulate electron transfer
conduits within preformed donor/acceptor adducts, resulting
in elevated ease of flow of reducing equivalents. Substrate-steered
ordering of the oligomeric aggregation state of P450s is likely
to impose steric constraints on heterodimers, causing one
component to more readily align with electron carriers. Careful
uncovering of electrochemical mechanisms in these systems
will be fruitful to tailoring of novel bioenergetic machines
and redox chains via redox-inspired protein engineering or
molecular Lego, capable of generating products of interest
or degrading toxic pollutants. Finally, availability of P450
nanobiochips for high-throughput screening of substrate libraries
might expedite drug development.
[Back to top]
N-Dealkylation of Arylpiperazine Derivatives: Disposition
and Metabolism of the 1-Aryl-Piperazines Formed
S. Caccia
In recent years several arylpiperazine derivatives have reached
the stage of clinical application, mainly for the treatment
of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine
buspirone, the chlorophenylpiperazine derivatives nefazodone
and trazodone, the dichlorophenylpiperazine aripiprazole and
the benzisothiazolyl derivatives perospirone and ziprasidone.
Most of them undergo extensive pre-systemic and systemic metabolism
including CYP3A4-dependent N-dealkylation to 1-aryl-piperazines.
These metabolites are best known for the variety of serotonin
receptor-related effects they cause in man and animals, although
some have affinity for other neurotransmitter receptors; others,
however, are still largely unexplored despite uncontrolled
use as amphetamine-like designer drugs. Once formed they distribute
extensively in tissues, including brain which is the target
site of most arylpiperazine derivatives, and are then primarily
biotransformed by CYP2D6-dependent oxidation to hydroxylates
which are excreted as conjugates; only 1-(2-benzisothiazolyl)-piperazine
is more susceptible to sulfur oxidation than to aromatic hydroxylation.
In studies analysing animal brain and human blood, 1-aryl-piperazine
concentrations were either higher or lower than the parent
compound(s), although information is available only for some
derivatives. At steady state, the metabolite-to-parent drug
ratios varied widely among individuals taking the same dosage
of the same arylpiperazine derivative. This is consistent
with the known individual variability in the expression and
activity of CYP3A4 and CYP2D6.
This review also surveys current published information on
physiological and pathological factors affecting the 1-arylpiperazine-to-parent
drug ratios and examines the potential role of 1-arylpiperazine
formation in the pharmacological actions of the arylpiperazine
derivatives that are already or will shortly be available
in major markets.
[Back to top]
Different Roles of Pummelo Furanocoumarin and Cytochrome
P450 3A5*3 Polymorphism in the Fate and Action of Felodipine
L.-Q. Guo, Q.-Y. Chen, X. Wang, Y.-X. Liu, X.-M. Chu,
X.-M. Cao, J.-H. Li and Y. Yamazoe
Objective: Herein we aim to test if pummelo furanocoumarins
can inhibit cytochrome P450 (CYP) 3A both in vitro
and in vivo, and to explore the influence of CYP3A5*3
(GenBank AC005020: A22893→G)
polymorphism in the pharmacokinetics and pharmacological response
to felodipine. Method: Fruit juices of pummelo grapefruit
(Citrus paradisi Macf., G), 'Guanximiyou' (C.
grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C.
changshanhuyou Y.B. Chang, H) were selected by screening
Citrus fruit juices for their furanocoumarin contents
and their inhibition of testosterone 6β-hydroxylation
in human liver microsomes. Twelve healthy male Chinese were
administered 250 mL G, P, H or water (W) alternatively with
26-μmol
(10-mg) plain tablet felodipine, and were observed for 12
h. Results: G had more furanocoumarins and at higher
levels than P while H had none, and their potencies for in
vitro CYP3A inhibition were in the order as G > P
> H. The geometric mean and 90% confidence intervals of
pharmacokinetic parameters for human oral felodipine with
G, P, H and W were respectively as follows: peak plasma concentration
(nmol•L-1), 37 (32-44),
25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma
concentration-time curve (nmol•h•L-1),
118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects
showed higher heart rates with G than with H or W. CYP3A5*3
polymorphism showed no significant effect on felodipine pharmacokinetics
and related hemodynamic changes. Conclusions: This
work supports the hypothesis that CYP3A inhibition by furanocoumarins
caused pummelo fruit juice-drug interaction; while the role
of CYP3A5 in the population pharmacokinetics of felodipine
and blood pressure response appear to be limited.
[Back to top]
The Regulation of Liver Cytochrome P450 by the Brain
Dopaminergic System
J. Wójcikowski, K. Golembiowska and W.A. Daniel
Genes encoding different cytochrome P450 (CYP) isoforms are
regulated by endogenous hormones (e.g. pituitary hormones,
thyroid hormones, glucocorticoids) which are all under control
of the central nervous system. The aim of the present study
was to investigate the influence of lesions of brain dopaminergic
pathways on the level and the activity of CYP isoforms (1A,
2A, 2B, 2C6, 2C11, 2D, 3A) in rat liver. At 48 h after lesion
of the tuberoinfundibular pathway, only the activity and the
protein level of CYP2B were significantly decreased. Seven
days after lesion of the above-mentioned pathway, significant
inhibition of CYP2B, CYP2C11 and CYP3A activities and a decrease
in CYP protein levels were observed. At the same time, the
activity and the protein level of CYP1A considerably increased.
Fourteen days after damage of the mesolimbic pathway, the
activity and the protein level of CYP3A were significantly
reduced, while those of CYP1A were substantially elevated.
In contrast, lesion of the nigrostriatal pathway did not affect
any CYP isoforms studied.
The obtained results provide the first direct evidence for
the influence of brain dopaminergic system on the level and
the activity of CYP in the liver, which is pathway- and isoform-dependent.
Hence stimulation or inhibition of the brain dopaminergic
system (e.g. by dopamine receptor-blocking neuroleptics) may
cause changes in CYP activity of physiological, pharmacological
and toxicological significance, since CYP isoforms that are
regulated by the dopaminergic system catalyze the metabolism
of endogenous substances (e.g. steroids), clinically important
drugs (e.g. psychotropics, calcium channel antagonists, antibiotics)
and toxins.
[Back to top]
Different Inflammatory Biomarker Patterns in the Cerebro-Spinal
Fluid Following Heart Surgery and Major Non-Cardiac Operations
H.J. Reis, A.L. Teixeira, J. Kálmán, G.
Bogáts, B. Babik, Z. Janka, M.M. Teixeira and A. Palotás
Cognitive decline occurs frequently after cardiac surgery
and it may lead to patient morbidity. The purpose of this
study is to focus on the static incidence of neuro-psychiatric
impairment associated with altered inflammatory biomarkers
in the cerebro-spinal fluid (CSF) that may provide an insight
into the mechanisms of acute peri-operative cognitive disturbances
related to heart surgery. Immuno-assays were used to evaluate
concentrations of several cytokines in CSF of patients undergoing
either off-pump coronary artery bypass grafting (OP-CABG)
or major non-cardiac surgeries. Inter-group analysis showed
no differences in baseline cytokine abundance. Levels of IL-8
have markedly increased both after OP-CABG and major non-cardiac
surgeries (34.59±7.15 vs. 99.45±6.35, and 27.44±7.17
vs. 66.63±15.18). Rantes showed significantly
greater quantity in CSF of the non-cardiac group after surgery
(8.71±3.37 vs. 114.56±65.42), whereas it became
somewhat less abundant in the post-operative period but statistically
unchanged in the OP-CABG cohort (19.87±15.71 vs. 9.37±3.65).
IP-10 and MCP-1 did not show significant changes in their
concentrations in either patient population (OP-CABG: 254.41±160.01
vs. 224.55±214.39, and 140.37±40.98 vs. 147.16±37.98;
non-cardiac: 274.99±219.44 vs. 395.09±468.30,
and 126.56±31.24 vs. 124.41±49.89, respectively).
These findings suggest that cardiac surgery provokes alterations
in the levels of various cytokines in the CSF, and the OP-CABG
induced changes in biomarker profile differs from that seen
after major non-cardiac surgeries. This, along with other
biomarkers, may offer an explanation for relationships between
the pronounced incidence of cognitive impairment after heart
operations.
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