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Current
Drug Metabolism
ISSN: 1389-2002
Current Drug Metabolism
Volume 9, Number 4, May 2008
Contents:
Environmental Impacts on Enzymes Involved in Drug and Steroid
Metabolism
Guest Editor: R.H. Waring
Editorial Pp. 267-268
R.H. Waring
Sulfotransferase Inhibition: Potential Impact
of Diet and Environmental Chemicals on Steroid Metabolism
and Drug Detoxification Pp. 269-275
R.M. Harris and R.H. Waring
[Abstract]
Effects of Plasticisers and Related Compounds
on the Expression of the Soluble Form of Catechol-O-Methyltransferase
in MCF-7 Cells Pp. 276-279
P.W.L. Ho, A.C.Y. Chu, K.H.H. Kwok, H.F. Liu, M.H.W. Kung,
D.B. Ramsden and S.L. Ho
[Abstract]
Flavin Mono-Oxygenase (FMO) - The ‘Other’
Oxidase Pp. 280-284
S.C. Mitchell
[Abstract]
Wide-Ranging Genomic Effects of Plasticisers
and Related Compounds Pp. 285-303
N. Turan, L.S. Cartwright, R.H. Waring and D.B. Ramsden
[Abstract]
Estrogenic Phenol and Catechol Metabolites of
PCBs Modulate Catechol-O- Methyltransferase Expression Via
the Estrogen Receptor: Potential Contribution to Cancer Risk
Pp. 304-309
P.W.L. Ho, C.E. Garner, J.W.M. Ho, K.C. Leung, A.C.Y.
Chu, K.H.H. Kwok, M.H.W. Kung, L.T. Burka, D.B. Ramsden and
S.L. Ho
[Abstract]
General Articles
Drugs Behave as Substrates, Inhibitors and
Inducers of Human Cytochrome P450 3A4 Pp. 310-322
Shu-Feng Zhou
[Abstract]
Species-Specific and Age-Dependent Bile Acid
Composition: Aspects on CYP8B and CYP4A Subfamilies in Bile
Acid Biosynthesis Pp. 323-331
K. Lundell and K. Wikvall
[Abstract]
Possible Role of Hydroxylated Metabolites of
Tacrine in Drug Toxicity and Therapy of Alzheimer´s
Disease Pp. 332-335
J. Patocka, D. Jun and K. Kuca
[Abstract]
A Carboxylesterase 2 Gene Polymorphism as Predictor
of Capecitabine on Response and Time to Progression
Pp. 336-343
N. Ribelles, J. López-Siles, A. Sánchez,
E. González, M.J. Sánchez, F. Carabantes, P.
Sánchez-Rovira, A. Márquez, R. Dueñas,
I. Sevilla and E. Alba
[Abstract]
Many Drugs and Phytochemicals Can Be Activated
to Biological Reactive Intermediates Pp. 344-351
W.W. Johnson
[Abstract]
An Experimental Approach for the Study of Psychotropic
Drug Effects Under Simulated Clinical Conditions
Pp. 352-360
N.N. Kudryavtseva, D.F. Avgustinovich, N.P. Bondar, M.V.
Tenditnik and I.L. Kovalenko
[Abstract]
Abstracts
[Back to top]
Editorial :Environmental Impacts on Enzymes Involved in Drug
and Steroid Metabolism
R.H. Waring
Although there has been much effort in recent years
to unravel the complications of pharmacogenetics in drug metabolism,
impacts which are ‘environmental’ in the widest
sense are also important and have been relatively neglected.
Typically, they underlie at least 20-30% of the variation
seen in any metabolic pathway within a human population but
because they often do not impact on the genome, the effects
are less easy to recognise. The input is multifactorial and
often comes from surprising sources, including diet [1], indoor
air [2], concomitant drug therapy [3], pesticides [4] industrial
accidents [5] urban dust particulate matter [6] and medical
devices [7]. Some environmental contributions are more obvious
than others or have clear therapeutic implications–
for instance the inhibition of CYP 3A4 by fruit juices and
grapefruit furanocoumarins has been investigated and shown
to affect the gastrointestinal first-pass metabolism of certain
statins as well as other drugs such as warfarin and felodipine
[8,9]. Aromatase (CYP2C19) is an isoform of cytochrome P-450
which converts androgens such as testosterone to oestrogens
such as oestradiol by catalysing the formation of the aromatic
(phenolic) ring which is the distinguishing feature of the
female steroid hormones. This pathway is a metabolic bottleneck
since it appears to be the only means of synthesising oestrogens
in mammals. Its inhibition is used in therapy for breast cancers
which are usually oestrogen-dependent [10]; drugs such as
anastrozole which are aromatase inhibitors are now in routine
use [11]. However, like many CYP isoforms, aromatase is inhibited
by dietary components at levels which may be physiologically
relevant [12]. The effects of environmental modulation of
CYP isoforms and glucuronyltransferases have recently been
described in several papers [12,13,14]; both these pathways
are central to drug metabolism but can be modulated by components,
often including flavonoids, from Brassica, Cruciferae, Allium
and other plant families. Dietary indoles and flavonoids can
activate CYP1A expression either by direct ligand interaction
with the arylhydrocarbon receptor (AhR) or by increasing the
interaction of the AhR with xenobiotic response elements in
CYP1A1 and other target genes. Interactions with pharmacogenetic
variation can also occur [5,15]; cruciferae interact with
the glucuronyltransferase polymorphism UGT1A1*28 which has
decreased UGT1A1 promoter activity due to 7 thymine-adenine
(TA) repeats although no interaction was seen with individuals
with the wild-type 6 (TA) repeats [15].
The contributions of dietary and environmental factors to
the activities of other pathways have been less well-explored
and this collection of articles focuses on a range of enzymes
which although they are not ‘the usual suspects’
are nevertheless main stream. Flavin monoxygenase (FMO-3)
catalyses the conversion of trimethylamine, which smells of
fish, to its N-oxide which does not [16]. Inhibition of this
enzyme may therefore affect the social interactions of the
individuals concerned and inspection of web-sites devoted
to perception of body odour (eg those for trimethylaminuria/’fish
odour syndrome’) shows that this can be a major problem.
The COMT (catechol-O-methyltransferase) isoforms act as methylating
agents using S-adenosylmethionine as donor. Oestrogens are
converted to 4-catechol oestrogens which can be metabolised
to their methoxy derivatives by COMT or oxidised to catechol
oestrogen-3,4-quinone metabolites. This process impacts on
carcinogenesis as the oestrogen quinone metabolites are believed
to react with DNA to form depurinating adducts and to induce
mutations. Reduced activity of COMT might therefore be a risk
factor for oestrogen-sensitive tumours and reduced expression
of COMT in breast tissue has been linked with a higher susceptibility
to breast cancer [17]. Inhibition of the COMT enzymes by a
range of common industrial pollutants may therefore be an
aetiological factor in this increasingly common disease. Recent
research has shown that many persistent organic pollutants
(POPS), including PCB metabolites and plasticisers, can inhibit
the various isoforms of the sulphotransferase (SULT) enzymes
[18]. In general, the addition of sulphate is a pathway for
detoxication/inactivation and endogenous compounds such as
dopamine and oestrogen give metabolites which are more water-soluble
and no longer active at the receptors. Many, although not
all, drug sulphate conjugates (Minoxydil is an exception)
are similarly inactive pharmacologically so that inhibition
of the SULT isoforms can alter both endogenous and xenobiotic
metabolism.
All these articles explore the effects of POPs as direct enzyme
inhibitors, actions which would not be found by genomic or
proteomic studies since alterations in gene/protein expression
are not involved. Recent research has shown that environmental
compounds have the capacity to alter the methylation status
of DNA sequences and so to affect gene expression. This then
raises the possibility that if environmental compounds could
be shown to alter DNA methylation in critical genes, then
they might alter drug or endogenous metabolism indirectly.
Phthalates are ubiquitous environmental contaminants and known
endocrine disrupters which affect rodents and man but have
only a very weak affinity with the steroid receptors and must
therefore have other mechanisms of action. Butylbenzylphthalate
(10-5 M) has been shown to
produce hypomethylation of the DNA at the promoter region
of the ERα
gene in MCF7 cells, as did the related dibutylphthalate [19].
Benzopyrene similarly deregulates gene expression by producing
hypomethylation at the p53 gene [20] while developmental exposure
to bisphenol A and estradiol increases susceptibility to prostate
cancer and affects the prostate epigenome by altering the
methylation status of phosphodiesterase type 4 variant 4 [21].
Other non-genetic factors silence the SULT1A1 gene, increasing
the methylation of both the proximal and distal SULT 1A1 promoters
in breast carcinomas and significantly reducing mRNA expression
[22]. As the SULT 1E1 gene is non-functional in many breast
cancers, silencing the SULT1A1 gene will substantially reduce
oestrogen inactivation by sulphation and so increase free
active steroid levels.
It seems clear then that environmental compounds can potentially
interact with the epigenome and the final article includes
evidence for the effects of POPs on the human genome and on
glycosylation. These techniques flag up a range of indirect
effects, highlighting the potential interactions of POPs with
expression of many transcription factors and cell-signalling
pathways which could modulate physiological responses to therapeutic
agents. Protein glycosylation is part of the wider process
of post-translational modification and has been shown to alter
enzyme activity and sustrate specificity [23,24]; although
the process is not fully understood it is obviously capable
of modification by POPs. It is clear that dietary components
and environmental contaminants can affect endo- and xeno-biotic
metabolism both directly and indirectly; depending on the
levels involved and the pathways affected, non-pharmacogenetic
factors may be critically important in the final physiological
response .
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[Back to top]
Sulfotransferase Inhibition: Potential Impact of Diet and
Environmental Chemicals on Steroid Metabolism and Drug Detoxification
R.M. Harris and R.H. Waring
The cytosolic sulfotransferase enzymes (SULT isoforms)
utilise PAPS (3’-phosphoadenosine-5’-phosphosulfate)
as co-factor to transfer sulfonate groups onto a wide range
of substrates. SULT1A3 has catecholamines such as dopamine
as substrates while SULT 1E1 sulfonates oestrogens. SULT 1A1
sulfonates phenols and also oestrogens at a higher Km
than SULT 1E1. SULT 2A1 mainly sulfonates DHEA
and some steroids, with hydroxy derivatives of polycyclic
aromatic hydrocarbons. Studies on these isoforms with a range
of environmental chemicals and dietary components have shown
that SULT 1A1 is significantly inhibited by flavonoids; all
flavones and flavonols with a 3’,4’-dihydroxy
motif had an IC50 of <
100nm against 3
μM 4-nitrophenol as the standard substrate. SULTs
1A3 and 2A1 were less strongly inhibited by flavonoids or
isoflavonoids although tricin (3’,5’-dimethoxy-4’,5,7-trihydroxyflavone
is a competitive inhibitor of SULT 1E1 with an inhibition
constant of ~1nM. Fruit and vegetable cytosols also inhibit
SULT isoforms, as do long-chain alkylphenols and chlorinated
phenols. Phthalates (used as plasticisers) inhibited SULTs
1E1 and 2A1. As these environmental contaminants and dietary
components all act at the same site, their effects would be
expected to be additive and could potentially therefore reduce
sulfonation of drugs and lead to altered pharmacological responses.
[Back to top]
Effects of Plasticisers and Related Compounds on the Expression
of the Soluble Form of Catechol-O-Methyltransferase in MCF-7
Cells
P.W.L. Ho, A.C.Y. Chu, K.H.H. Kwok, H.F. Liu, M.H.W. Kung,
D.B. Ramsden and S.L. Ho
Previously we have shown that E2 down regulates S-COMT
expression. Here the effects of four phthalate esters and
4-(tert-octyl)phenol on the intra-cellular levels of S-COMT
and COMT activity were studied in MCF-7 cells as a measure
of estrogenic activity of these compounds. The four phthalate
esters caused significant reductions in both S-COMT protein
and COMT activity levels. These effects were inhibited by
the ERα
receptor antagonist ICI182780. 4-(tert-octyl)phenol also caused
reductions in these parameters, but the effects were not abolished
by ICI182780. Assay of S-COMT protein levels represents a
simple and convenient method of assessing the estrogenic potential
of a compound.
[Back to top]
Flavin Mono-Oxygenase (FMO) - The ‘Other’
Oxidase
S.C. Mitchell
Whilst the scientific community was celebrating the truly
momentous discovery of a ‘mixed function oxidase’
another oxidase was quietly working behind the scenes, mopping
up soft nucleophiles and, as it had undoubtedly being doing
for aeons, aiding then unknown in the metabolism of xenobiotics
and the protection of life forms. This enzyme, flavin mono-oxygenase,
has subsequently been shown to be a major player, if not yet
an equal partner with cytochrome(s) P450, in the metabolism
of both endogenous biochemicals and foreign compounds that
enter the human organism. This article outlines the importance
of the flavin mono-oxygenases and examines their susceptibility
to activity modulation by exogenous factors.
[Back to top]
Wide-Ranging Genomic Effects of Plasticisers and Related Compounds
N. Turan, L.S. Cartwright, R.H. Waring and D.B.
Ramsden
The effects of four compounds, bis(2-ethylhexyl)phthalate
(BEHP); diisodecylphthalate (DIP); 4-n-octylphenol (OP); 4-chloro-3-methylphenol
(CMP), on gene expression (steady-state mRNA levels) across
the whole human genome were studied in human TE671 cells.
Effects were studied using the Affymetrics GeneChip®
Human Genome U133 Plus 2.0, HG-U133
Plus 2.0 arrays, The array analyses the expression of 47,000
transcripts and variants, including ~38,500 well characterised.
All four compounds exerted statistically significant actions,
affecting between 4 and 6.5% of all genes. Each compound had
its own expression signature. In most instances where there
was an effect steady-state mRNA levels were decreased, although
not always. CMP reatment caused most increases in mRNA levels.
.A mixture of DIP and CMP caused fewer changes in mRNA levels
than either of the individual compounds.
Conclusions: These plasticisers affected the steady-state
mRNA levels of many human genes. Exposure to these compounds
over many years has the potential to influence human health.
[Back to top]
Estrogenic Phenol and Catechol Metabolites of PCBs Modulate
Catechol-O- Methyltransferase Expression Via the Estrogen
Receptor: Potential Contribution to Cancer Risk
P.W.L. Ho, C.E. Garner, J.W.M. Ho, K.C. Leung, A.C.Y.
Chu, K.H.H. Kwok, M.H.W. Kung, L.T. Burka, D.B. Ramsden and
S.L. Ho
Commercial PCB mixtures have been shown to induce liver tumors
in female rats and this effect has been attributed to the
effects of PCBs on estrogen metabolism. Catechol metabolites
of PCBs are potent inhibitors of COMT activity and are likely
to contribute significantly to reduced clearance of genotoxic
catechol metabolites of estrogen. The effect of PCB metabolites
on COMT expression in cultured cells was investigated to explore
potential mechanisms by which PCB exposure alters catechol
estrogen clearance. We hypothesize that estrogenic PCB metabolites
may contribute to reduction of COMT expression via interaction
with the estrogen receptor. To test this hypothesis, human
MCF-7 cells were exposed to PCB analogues and the expression
of COMT determined. Western blot analysis demonstrated that
COMT protein levels were statistically significantly reduced
by both the phenolic and the catechol compounds, an effect
which was abolished by the anti-estrogen, ICI182780. The above
suggests that COMT levels may be reduced by estrogenic PCB
metabolites, via interactions between PCB metabolites and
the ER. It supports the hypothesis that both phenolic and
catechol metabolites of PCBs may contribute to PCB-mediated
carcinogenesis through reduction of COMT levels and activities
and subsequent reduction in clearance of endogenous and xenobiotic
catechols.
[Back to top]
Drugs Behave as Substrates, Inhibitors and Inducers of Human
Cytochrome P450 3A4
Shu-Feng Zhou
Human cytochrome P450 (CYP) 3A4 is the most abundant
hepatic and intestinal phase I enzyme that metabolizes approximately
50% marketed drugs. The crystal structure of bound and unbound
CYP3A4 has been recently constructed, and a small active site
and a peripheral binding site are identified. A recent study
indicates that CYP3A4 undergoes dramatic conformational changes
upon binding to ketoconazole or erythromycin with a differential
but substantial (>80%) increase in the active site volume,
providing a structural basis for ligand promiscuity of CYP3A4.
A number of important drugs have been identified as substrates,
inducers and/or inhibitors of CYP3A4. The ability of drugs
to act as inducers, inhibitors, or substrates for CYP3A is
predictive of whether concurrent administration of these compounds
with a known CYP3A substrate might lead to altered drug disposition,
efficacy or toxicity. The substrates of CYP3A4 considerably
overlap with those of P-glycoprotein (P-gp). To date, the
identified clinically important CYP3A4 inhibitors mainly include
macrolide antibiotics (e.g., clarithromycin, and erythromycin),
anti-HIV agents (e.g., ritonavir and delavirdine), antidepressants
(e.g. fluoxetine and fluvoxamine), calcium channel blockers
(e.g. verapamil and diltiazem), steroids and their modulators
(e.g., gestodene and mifepristone), and several herbal and
dietary components. Many of these drugs are also mechanism-based
inhibitors of CYP3A4, which involves formation of reactive
metabolites, binding to CYP3A4 and irreversible enzyme inactivation.
A small number of drugs such as rifampin, phenytoin and ritonavir
are identified as inducers of CYP3A4. The orphan nuclear receptor,
pregnane X receptor (PXR), have been found to play a critical
role in the induction of CYP3A4. The inhibition or induction
of CYP3A4 by drugs often causes unfavorable and long-lasting
drug-drug interactions and probably fatal toxicity, depending
on many factors associated with the enzyme, drugs and the
patients. The study of interactions of newly synthesized compounds
with CYP3A4 has been incorporated into drug development and
detection of possible CYP3A4 inhibitors and inducers during
the early stages of drug development is critical in preventing
potential drug-drug interactions and side effects. Clinicians
are encouraged to have a sound knowledge on drugs that behave
as substrates, inhibitors or inducers of CYP3A4, and take
proper cautions and close monitoring for potential drug interactions
when using drugs that are CYP3A4 inhibitors or inducers.
[Back to top]
Species-Specific and Age-Dependent Bile Acid Composition:
Aspects on CYP8B and CYP4A Subfamilies in Bile Acid Biosynthesis
K. Lundell and K. Wikvall
The present review aims to give an overview of the cytochrome
P450 8B (CYP8B) and cytochrome P450 4A (CYP4A) sub-families
in relation to biosynthesis of bile acids, in particular trihydroxy
bile acids. Trihydroxy bile acids are basically required in
most species and have an impact on cholesterol and lipid metabolism.
The primary trihydroxy bile acid in most mammals is cholic
acid. Some species produce other important trihydroxy bile
acids, for example the adult pig which produce hyocholic acid
instead of cholic acid. The position of the third hydroxyl
group in cholic acid and hyocholic acid, 12α
or 6α
position, respectively, has a profound effect on the hydrophilic-hydrophobic
property of the trihydroxy bile acids. The CYP8B subfamily
is required for introduction of the 12α
-hydroxyl group in cholic acid biosynthesis. The enzyme responsible
for 6α-hydroxylation
in hyocholic acid biosynthesis, however, varies among species.
This review will discuss, in particular, porcine members of
the CYP8B and CYP4A subfamilies because interesting findings
regarding members of these subfamilies have recently been
recognized in this species. CYP8B1 was for a long time believed
to be absent in the pig but was recently found to be expressed
in fetal pig liver. The enzyme catalyzing the 6α
-hydroxylation in hyocholic acid biosynthesis in pig was found
to be an atypical member of the CYP4A subfamily, denoted CYP4A21.
The review presents bile acid biosynthesis in view of these
findings and discusses physiochemical properties and developmental-dependent
aspects related cholic acid and hyocholic acid biosynthesis.
[Back to top]
Possible Role of Hydroxylated Metabolites of Tacrine in Drug
Toxicity and Therapy of Alzheimer´s Disease
J. Patocka, D. Jun and K. Kuca
Tacrine belongs to the group of acetylcholinesterse (AChE)
inhibitors used as drugs for treatment of Alzheimer´s
disease (AD). The formation of hydroxyderivatives of tacrine
is well-established step in the metabolization of this drug
in liver by microsomal cytochrome P450 enzymes family. Genetic
polymorphism of cytochrome P450 enzymes is probably responsible
for balance between a number of stable and non-toxic metabolites
and highly protein-reactive and toxic ones. By this manner
may be explained why the hepatotoxicity of tacrine was observed
only in the part of persons and why not every patient with
AD responds to the treatment by this drug.
[Back to top]
A Carboxylesterase 2 Gene Polymorphism as Predictor of Capecitabine
on Response and Time to Progression
N. Ribelles, J. López-Siles, A. Sánchez,
E. González, M.J. Sánchez, F. Carabantes, P.
Sánchez-Rovira, A. Márquez, R. Dueñas,
I. Sevilla and E. Alba
Capecitabine is a drug that requires the consecutive
action of three enzymes: carboxylesterase 2 (CES 2), cytidine
deaminase (CDD), and thymidine phosphorylase (TP) for transformation
into 5-fluorouracil (5FU). The metabolism of 5FU requires
the activity of thymidylate synthase (TS) and dihydropyrimidine
dehydrogenase (DPD) among other enzymes. The present study
prospectively examined the possible relationship between the
toxicity and efficacy of capecitabine and 14 different polymorphisms
in CES 2, CDD, TS and DPD. Between 2003
and 2005, a total of 136 patients with advanced breast or
colorectal cancer treated with capecitabine were prospectively
enrolled. The presence of two polymorphisms (CDD 943insC and
CES 2 Exon3 6046 G/A) were associated with a non-statistically
significant higher incidence of grade 3 hand-foot syndrome
(HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively.
Patients heterozygous or homozygous for the polymorphism CES
2 5’UTR 823 C/G exhibited a significantly greater response
rate to capecitabine, and time to progression of disease (59%,
8.7 months) than patients with the wild type gene sequence
(32%, p=0.015; 5.3 months, p=0.014). For the first time, an
association between a polymorphism in the CES2 gene
and the efficacy of capecitabine has been described, providing
preliminary evidence of its predictive and prognostic value.
[Back to top]
Many Drugs and Phytochemicals Can Be Activated to Biological
Reactive Intermediates
W.W. Johnson
The metabolism of drugs and other xenobiotics is exemplified
by cytochrome P450-mediated oxidation to more hydrophilic
compounds. Enzymatic oxidation of some functional groups,
however, can result in transient reactive intermediates --
a transformation that is common in nature. Some drugs and
many phytochemicals that contain, for example, a thiophene
ring are oxidized by cytochrome P450 to reactive intermediates,
such as sulfoxides, that can covalently bond to thiol nucleophiles
in macromolecules, such as proteins. Many other functional
groups can be oxidized to reactive intermediates -- for instance,
olefins, alkynes, alkylamines, furans, and p-aminophenols.
Because any consequence of a biological reactive intermediate
(BRI) is dependent on many factors a number of BRIs are benign.
Toxicity is determined by complex and specific arrays of parallel
and/or serial pathways and cellular states, not by entities
or individual reactions. Because the formation of reactive
intermediates can correlate with unacceptable toxicity, it
is important to understand if or how a compound may undergo
this type of transformation. Not all substances that form
reactive intermediates are toxic; many are not. Therefore,
it is critical to understand the mechanism of metabolism in
considering any toxicity relevance and in evaluating animal
models. Indeed, the complex nature of these many interactions
and entities underscores the fact that the presence of a BRI
is not an accurate indicator of human toxicity. A BRI is neither
good nor a priori bad. It is a potential detoxication
product and an incidental fate of the xenobiotic.
[Back to top]
An Experimental Approach for the Study of Psychotropic Drug
Effects Under Simulated Clinical Conditions
N.N. Kudryavtseva, D.F. Avgustinovich, N.P. Bondar, M.V.
Tenditnik and I.L. Kovalenko
The sensory contact model can induce various different
psychopathological states in male mice (anxious depression,
catalepsy, social withdrawal, pathological aggression, cognition
disturbances, anhedonia, alcoholism etc.). Additionally, this
model facilitates the screening of drugs for therapeutic properties,
preventive properties and efficiency under simulated clinical
conditions. This approach can reveal the action of drugs at
different stages of disease development. It is proposed that
this pharmacological approach can be applied for the screening
of various novel psychotropic drugs.
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