In this holiday, i am so bored that it drives me to do some hardcore reading. i had read through few reputable journals. And after reading those journals i had decided to summarize what i had learnt in this blog. The title of this article/post/portfolio is “Metal complexes in
biological systems”. Which i found it will be interesting and useful to those people who are interested in research.
So what is meant by biological molecule? A bioorganic molecule is defined as an organic molecule which is found
in living organisms. Bioorganic chemistry is a cross discipline between biology
and chemistry, it is relatively new field to be explored. Metallic elements are essential for many of the
processes in life.
Sodium, potassium, calcium,
and magnesium are known as minerals because they are essential and are required
in large quantities.
Metals which are required in
small amount < 0.01% of the body mass are known as
trace metals.
Examples of them are lithium,
cobalt, nickel, and zinc. These metals can combine with bioorganic molecule to
form a new complex.
A. Cytochrome
P450 Enzymes
The first metal-bioorganic complexes in biological
system which I am discussing here is Cytochrome P450 Enzymes or CYP450. CYP450
is known hemoproteins ,this is because it belongs to the superfamily of protein
that contains heme as a cofactor. The cofactor heme contains an iron center,
which is tethered to the CYP450 protein via thiolate ligands. CYP40 is an
important class of enzyme, this is because it metabolizes majority of the
endogenous and exogenous chemicals. It performs these by the process called
oxidation. This class of enzyme utilizes the redox chemistry of the Fe3+/Fe2+
couple for the activation of oxygen (O2) molecules. Oxygen (O2)
is been split into two oxygen atoms ,but only one out of two of the oxygen atoms
is been used for the oxidation of substrates (can be exogenous or endogenous
chemicals), while the second oxygen atom is been used to form H2O as
a by-product.
RH + O2 + NADPH + H+ ----- >ROH + H2O
+ NADP+
First, I
would like to discuss on a journal published on July 2000, I found this journal
very interesting because it integrated the knowledge and skills we acquired in
Semester 4 Central Nervous System , Medical Chemistry, Biotechnology and
Statistics. I love this journal very much. It can be served as reference for
further research purposes in IMU. The title of this journal is “The Cytochrome
P450 2D6 (CYP2D6) and Serotonin Transporter (5-HTT) Polymorphisms in depressed
Inpatients compared to a Control Group”. This study was carried out by a group
of leading researchers named, Professor W Steimer, Dr B Müller,Professor S
Leucht, W Kissling and their members. The institutes and departments involved
in this research were Institute for Clinical Chemistry and Pathobiochemistry ,
Department of Psychiatry and Psychotherapy ,and Munich University of
Technology, Germany. The purpose of this study was to discover the
relationships between genetic differences among different individuals (which
will directly affects the CYP450 expressed) with the treatment of non-psychotic
depressions using the selective serotonin reuptake inhibitors ,SSRIs. Cytochrome P450 (CYP450) enzymes
play a role in the metabolisms of selective serotonin reuptake inhibitors
(SSRI) antidepressants. According to the researchers Professor Mugdha Thakur
and Professor Iris Grossman, these
effects will directly affect the prognosis of the depression treatment as well
as the degree of adverse effects experienced by our patients. Thus, if a
positive results can be obtained then more time and funds should be spent in the
development of individualized and anti-depressants which is more specific.
A significant number of
depressed patients which had been treated with Tricyclic Antidepressants (TCA)
and Selective Serotonine Reuptake Inhibitors (SSRI) had been said to be
non-responsive towards these treatments. Thus a research and study had been carried
out. In this study, few advance biotech
techniques had been applied, named nested multiplex sequence specific PCR and
long PCR for the detection of CYP 2D6 polymorphisms (*3 to *8 and duplication)
, besides that conventional PCR for the determination of the long and short
variants of the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also
applied. These genetic study techniques were applied because the genetic
polymorphisms of cytochrome P450 2D6 enzymes(responsible for the metabolisms of
Tricyclic Antidepressants) and the promoter of the serotonin transporter gene
(SSRIs) have been said to play a role in these non-responsiveness.
In this research 75 depressed
inpatients were randomly picked as sample of study, and 159 anonymous made up
of 115 hospital staffs and 45 medical students were treated as control samples.
Their DNA samples were extracted out from leukocytes by standard methods
(learned in sem 4 biotech). Later the genes responsible for CYP450 2D6 were
been amplified using the unique primers designed together with the help of
Polymerase Chain Reaction thermocycle machines. The genes responsible for
CYP450 2D6 were then treated with restriction enzymes, giving to us many genes
fragments of different length and bases.
Finally, the resulting fragments of the various PCRs were separated on
standard agarose gels (1.5% and 0.7%) and visualized by ethidium bromide
staining. The bands they obtained under X-rays were then analysed.
The results they obtained shown that out of 75
depressed inpatients 41 of them were having extensive metabolizers (EM) which
were wild types of genes, 19 were having
intermediate metabolizers (IM) which were heterozygotes types of genes,
8 out of 75 were having ultra-rapid metabolizers (UM), 5 poor metabolizers (PM)
and the other 2 patients were having a combined duplication and defect
mutations. The number of ultra-rapid metabolizers was significantly higher in
patients than in controls, with chi2:p les than 0.01. Later blood tests were
conducted for EM, IM, UM and PM patients. The results obtained shown that the
serum concentrations of TADs and SSRIs were higher in PM patients, normal in EM
and IM patients, but is lower in UM (ultrametabolizer) patients. These had
proved to us that the therapeutic effects of TCAs and SSRIs were directly
affected by CYP450 2D6 polymorphism. Ultra-metabolizer patients were Those patients who were
unresponsive to TADs and SSRIs treatments are usually those with ultra-metabolism
CYP450 2D6, whereas, the poor metabolizers are the group of patients who
suffered more therapeutic side effects. (chi2: p < 0.01)
<PLEASE EMAIL davidlaw0409@hotmail.com AND SUBSCRIBE TO ME IN ORDER TO STUDY THE TABLE>
From the
table above we can conclude by saying that the numbers of CYP450 2D6
polymorphisms are higher than those in healthy individuals. Besides that, the
phenotypic studies and classifications had revealed that the number of ultra-rapid
metabolizers was significantly higher in the patients group than in the control
group. This implies to us that the polymorphisms and ultra-rapid metabolisms
phenotypes may be a reason for the treatment failure in these depressed
patients.
On
the other hand, the result for 5HTT test shown no significant differences in
the patients and controls. There is no direct relationship between 5HTT genes
and SSRI
therapeutic failures.
Repeated changes of medications as
well as dose adjustments for both UM and PM patients are needed in order to
increase the treatments efficacy and minimizing the therapeutic side effects.
Co-therapy of SSRI with other substrates of CYP2D6 can also be a choice for UM
patients.
Next, I am discussing on a journal
titled Hepatic Lipid Peroxidation and Cytochrome P-450 2E1 in Pediatric
Nonalcoholic Fatty Liver Disease (NFLD) and Its Subtypes. This studywas done by
Professor Lauren N. Bell, Dr Jean P.
Molleston, Dr Michael J. Morton, and their group members. This study was aimed
to establish a relationship between CYP450 2E1 and hepatic lipid peroxidation
with non-alcoholic fatty liver disease in paediatrics. This study was carried
out at the Pediatric Liver Clinic at Riley Hospital for Children (Indianapolis,
IN). CYP450 2E1 enzymes are enzymes which responsible for normal metabolisms,
but if they are over-expressed the oxidations may lead to liver damage. On the
other hand, hepatic lipid peroxidations are processes by which the free
radicals in the body withdraw the electrons from the phospholipid bilayers
membranes of liver cells, leading to liver damage by oxidations.
All together there were 78 children
under the ages of 19 were included in this study. 59 of them were having NFLD,
9 of them were having chronic hepatitis C disease, and another 10 children with
normal liver biopsies were treated as control group. Their previous liver
biopsies were collected and analyzed. Hepatic malondialdehydes (a measure of lipid
peroxidation) levels and CYP2E1 proteins contents were quantitated, as a
percentage of the total area, by immunohistochemical staining of livers
biopsies collected from different children followed by digital image
quantitation.
The results obtained had proved to
us that hepatic lipid peroxidation, but not CYP2E1 protein content, is raised
in children with NFLD compared to those with normal liver histology or chronic
HCV infection. This also shown to us that there are some differences in the
pathophysiology of NFLD in children with that of adult. With the new
understanding of pathophysiology established ,a more specific therapies
targeting the oxidative stress like free radicals can be designed for children.
The third journal I am going to
share here is CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in
Asian breast cancer patients. Tamoxifens are anti-breast cancer drugs. Before
any pharmacological actions, they must first be metabolized into their active
metabolites called 4-hydroxytamoxifen and endoxifen, this conversions are
carried out by multiple cytochrome P450 (CYP) enzymes including CYP2D6,
CYP3A4/5, CYP2C9/19, CYP1A2 and CYP2B6. This study is to investigate the impact
of genetic polymorphisms in CYP2D6, CYP3A5, CYP2C9 and CYP2C19 on the
pharmacokinetics of tamoxifens, which will directly affect the serum
concentrations of their metabolites in Asian breast cancer patients.
Now I am going to summarize the
methods used for this study. There are a total of 393 subjects participated in
this study. 165 of them are Asian breast cancer patients receiving 20mg
tamoxifen daily and the rest (228) of them are made up of healthy Asian
subjects (Chinese ,Malay and Indian), these healthy patients were used as
control for this study. CYP2D6 polymorphisms of all the samples were genotyped
using the INFINITI™ CYP450 2D6I assay, while the polymorphisms in CYP3A5,
CYP2C9 and CYP2C19 were determined via direct sequencing. The blood samples of
patients were collected respectively and were analysed using high-performance
liquid chromatography in order to quantified the steady-state plasma
concentrations of tamoxifens and their metabolites.
There were no significant relationships
observed between polymorphisms of CYP3A5, CYP2C9 ,CYP2C19 and the metabolisms
of tamoxifens and metabolites of tamoxifens. On the other hand, polymorphisms
of CYP2D6 were said to have direct effects on the metabolisms of tamoxifens and
the serum concentrations of their metabolites. The polymorphisms, CYP2D6*5 and
*10, were significantly associated with lower endoxifen and higher
N-desmethyltamoxifen (NDM) concentrations. Besides that, the endoxifen
concentrations were found to be 1.8- to 2.6-times higher in *1/*5 or *1/*10
carriers compared with *10/*10 and *5/*10 carriers .Patients who were *1/*1
carriers exhibited 2.4- to 2.6-fold higher endoxifen concentrations and 1.9- to
2.1-fold lower NDM concentrations than either *10/*10 or *5/*10 carriers .
Thus, the pharmacists can actually
develop a treatment regimens which are specific for our patients, for example
those with gene polymorphisms at CYP2D6*5 and *10 should be given with
artificial direct endoxifens ,this is because the polymorphism they having
actually decreases the endoxifens level in their blood. Similarly, the unwanted
effects due to the excess high of NDM metabolites resulted from gene
polymorphism in these patients can be reduced by adjusting the doses of
tamoxifens administered, or others drugs can be used as prophylaxis of these
adverse effects.
Metallothioneins (MTs)
are low molecular weight proteins ranging from 500 to 14000 Da. They are
classified under the family of cysteine-rich proteins. They are found in the
membrane of Golgi apparatus. They have the abilities to bind with many metals both
physiological such as zinc, copper, selenium, as well as xenobiotic heavy
metals such as cadmium, mercury, silver, arsenic through the thiol groups of their
cysteine residues. Cysteine is a sulfur-containing amino acid, hence the word
“–thionein” was incorporated into “metallothioneins. The cysteines residues
made up of nearly one third of their total amino acidic residues.
MTs play important roles in metal
binding. Metallothioneins can bind to a wide range of metals including cadmium,
zinc, mercury, copper, arsenic, silver, etc. Metal-binding of MT occurs via a
sequential, non-cooperative mechanism. Some MTs only bind partially to metals
but the rest bind completely to the metals. Metallothioneins also participate
in the uptake, transport, and regulation of zinc in biological systems. Each mammalian
MTs binds and holds four Zn(II) ions in the alpha domain and three in its beta
domain. Most MTs in bacterials eg histidine participates in zinc binding. By
binding and releasing zinc, metallothioneins (MTs) may regulate zincs levels
within the body. Zincs, in turns, play the keys roles for the activation and
binding of transcription factors to DNA. Before zincs can activate the
transcription factors they should bind to the zincs fingers regions of MTs
proteins. Obviously, MTs do help to regulate tumor suppressor proteins p53 by
controlling the processes of transcriptions and genes expressions. Third, Metallothioneins
also play important roles in carrying zinc ions (signals) from one part of a
cell to another part of it. When zinc enters a cell, it will bind to
metallothionein protein and form
metallothionein. Metallothioneins will
be carried to another part of the cell where zinc is released from it to
another organelle or protein. Thus, MTs are important in the regulations of
neurons’ zincs signaling between and within nerve cells.
First,
I am going to discuss on a research article titled “New Proteins Found
Interacting with Brain Metallothionein-3 Are Linked to Secretion” written by
IssamEl Ghazi, Bruce L.Martin, and IanM. Armitage. I found out that this
article is interesting and can be served as reference for further research
purposes in IMU. In a previous study
conducted by Uchida et al ,using brain extraction of alzheimer’s sample (rat)
and normal sample (also rat). They found out that neurotrophic effect in the brain extract of
Alzheimer’s disease (AD) sample was higher than that in normal control sample.
High neurotrophic effect subsequently leads to the reduction of a protein
originally called, growth inhibitory factor (GIF). GIFs were first thought to
be involved in the formation of senile plaques, leading to the exhaustion of
the neurons and raised the susceptibility of these neurones to the damages from
exocitotoxic substances. But latter they found out in a follow up study that it
was the reduction of the GIFs activity and the presence of neurofibrillary
tangles (not with the senile plaques)
which lead to Alzheimer’s diseases. Further interpretation of this GIFs structure
by the process of isolation, purification, and sequencing revealed that GIFs
actually belonged to a class of protein, known as metallothionein (MT). As only
the third isoform of MT had been isolated and purified ,the name
metallothionein-3 (MT-3) was given to GIF. In 2010, again Uchida and his group
members decided to find out whether there are any special proteins in the body
which are able to stimulate the release of MT-3 in the brain, thus giving
neuroprotectivity to the brains of Alzheimer’s patients. They conducted this
research by 5 major processes. The first process was brain proteins extractions
from a rat. This step enabled them to collect all types of proteins sample
found in the brain. The second step involved Affinity Chromatography, in which
the samples extracted were analyzed. This technique allowed them to separate
proteins of different types, as well as allow them to measure their individual
fractions in the brain. The third step involves SDS-PAGE and In-Gel Trypsin
Digestion. This step was for them to digest the bands and also for them to
collect the supernatant. The fourth step involved Mass Spectrometry Analysis.
This step was important for them to know the identities of the sample proteins.
The mass spectra were later been analyzed using BioWorks SeQuest Analysis
Software package so that the functions of sample proteins extracted can be
predicted. The results obtained were recorded and discussed on the next page:
Protein ID MALDITOF MS/MS Function
Exo84p x
Transport
ATP
synthase βsubunit
x x Transport
Valosin
containing
Protein
x
HSP
84 x x
Chaperoning
HSP70
glucose-regulated
Protein x Chaperoning
HSP70
protein 8
x Chaperoning
Tubulin
alpha 3
x Scaffold
γ-Actin x
β-Actin
x x Scaffold
14-3-3
zeta x x Scaffold/regulation
Pyruvate
kinase 3
x Glycolytic metabolism
γ-Enolase x Glycolytic metabolism
α-Enolase
x x Glycolytic metabolism
Creatine
Kinase BB x x Glycolytic metabolism
Aldolase
3
x
Aldolase
1 x x Glycolytic metabolism
Malate
dehydrogenase x x Glycolytic metabolism
DRP-2 x x Neuronal growth
DRP-3 x
MT-3
by itself is not toxic nor does it inhibit the growth of neurons. Indeed, it
maintains the survival of neurons in culture. MT-3 knockout mice show a higher
susceptibility to kainic acid induced neuronal injury, while mice
overexpressing MT-3 show enhanced resistance. These results suggested that MT-3
may play a neuroprotective role against toxic substances. MT-3 is abundantly
expressed in astrocytes of normal brain, and according to the results obtained
above their secretions can be enhanced by giving or raising the expression of
others proteins which can interact with MT-3 and help in the transport and
release of MT-3. These proteins include Exo84p,Rab3a and ATP synthase βsubunits
(as shown on the table above). Thus
a revolution in the preventions and treatments of Alzheimer’s diseases may soon
be occurred, by targeting on the expression of the MT-3 and special proteins
listed above.
The
second journal which is related to metallothoneins is “Hepatic Metallothionein in
Patients With Chronic Hepatitis C: Relationship With Severity of Liver Disease
and Response to Treatment”. The study of this journal was carried out by Prof
Georges Carrera et.al. The aim of this study was to study the relationships
between hepatic levels and MTs levels in the livers of different patients.
Besides that, the distributions of MTs in hepatitis C virus (HCV) infected
livers were also studied. Reactive oxygen species involved in the mechanisms of
chronic hepatitis C virus infection. Metallothionein (MT) plays a key role in
the protection of cells against reactive oxygen species.
In this study, 32 patients with
chronic HCV infections were involved. Besides that a control group made up of
12 healthy subjects were also assigned.
Their respective liver biopsies samples were collected. MTs in the
samples were quantified separately using radioimmunoassay. Wherease,
Interleukin IL-1, IL-6, and tumor necrosis factors INF were quantified using
the technique of reverse transcription–polymerase chain reaction
(PCR). And not to forget, the cellular distribution
was also studied, and the technique used was immunohistochemistry.
In
this study, there were no correlations been found between MTs of chronic HCV
infected patients and intra-hepatic cytokine mRNA expression. Nevertheless,
they observed that the livers’ MTs proteins in HCV-infected patients were
3-fold lower than that of healthy control subjects. In addition to that, a
significant inverse linear regressions between MT proteins or mRNAs expressions
with the Histological Activities Indexes, the necro-inflammatory grades, as
well as the stages of fibrosis were obtained. These relationships had proved to
us that MT proteins play important role in suppressing the histological
activities, necro-inflammations, and fibrosis developments. From the study,
they also found that MTs immunostainings were located in the nucleuses and
cytoplasms of the liver cells of healthy control subjects, whereas those of
HCV-infected patients were been found in cytoplasms of the liver cells.
They
also found out that those patients given with interferon (IFN) anti-virus
therapies but did not respond well to the treatments had less MTs level than
those who responded to the therapies. (about half of the total MTs level in those
who responded to the interferon therapies
This study shows to us that the
hepatic MT expression could reflect the severity of chronic HCV infection
.Besides that, the levels of MTs can also affect the susceptibility of a
healthy person towards the HVC
infections. MTs levels also affect the prognosis of an individual upon starting
of Interferon therapies. May be doses adjustments should be done according to
the MTs levels in patients, so that safe therapeutics doses can be established
for maximum therapeutics outcomes.
The
third metallothionein I am sharing here is “Change of Zinc, Copper, and
Metallothionein
Concentrations and the Copper-Zinc Superoxide
Dismutase Activity in Patients With Pancreatitis”. This study was carried out
by Professor Halina Milnerowicz and his research team.
This study was aimed to measure
and correlate the concentrations of metallothioneins, zincs, coppers, as well
as Cu/Zn superoxide dismutase activities to chronic exacerbated pancreatitis
and chronic pancreatitis. The concentrations of these proteins and metals will
affect the balance of pro-oxidative and anti-oxidative activities in living
organisms . Professor Halina Milnerowicz and his research team had measured the
concentrations of metallothioneins by using the method of immune-enzymatic .On
the other hand, serum Cu/Zn superoxide dismutases activities were determined by
using commercial test. The measurements of Zincs and Coppers concentrations in
serums were assessed with the help of flame atomic absorption spectrometry. The
results and observations they obtained had shown that the serum Zincs
concentrations had been lowered but the Coppers levels had been raised in the
serum of patients with chronic exacerbated pancreatitis and chronic
pancreatitis. Besides that, significant increase of metallothioneins
concentrations and Cu/Zn superoxide dismutase activities (but still lower that
pro-inflammatory activities) were also been observed in the blood of these
patients. In addition to that, by observing the slices obtained from the
pancreases of patients with chronic exacerbated pancreatitis and chronic
pancreatitis, they found out that there are many immunohistochemical reaction
occurred, involving the actions of Cu/Zn superoxide dismutases and
metallothioneins.
All these results and
observations prove to us that the presences of variable antioxidants like Cu/Zn
superoxide dismutases and metallothioneins are important for a healthy
pancreas. Any disorder or dysfunction affecting the homeostasis of
metallothioneins , Cu/Zn superoxide dismutases, coppers and zincs will lead to
inflammatory processes and thus causing pancreatitis. On the other way, we can
also say that patients at different stages of pancreatitis will be having
different degrees of metallothioneins , Cu/Zn superoxide dismutases , zincs,
and coppers levels imbalances. So a treatment targeting on the recovery of
these imbalances can be developed for the treatment and prevention of
pancreatitis.
Next I am going to discuss on the biochemistry of zinc. Biochemistry of
zinc means the chemical reactions and biological processes happen
inside the body with the involvement of zinc. Zinc is classified as metal,
because it can conduct electricity and heat. Zinc is the 24th most abundant
element in the Earth's crust and has five stable isotopes. It is the first
element in group 12 of the periodic table. It has an atomic number of 30. Both
zinc and magnesium are having similar chemical properties. This is because its’
ion is having common oxidation number (+2) as magnesium ion. Although zinc is
an element but it usually exists in the form of zinc ore examples, zinc sulfide
mineral. In human body, zinc is required in trace amount , < 0.01% of total
body mass. Since zinc is a very reactive metal, it is very useful in industrial
field. It can be used as anti- corrosive agent for other corrosive metals.
Zincs are used in battery and protection of cars’ metals surfaces. Zincs when
mixed with coppers will form alloys called bronze, which are stronger, more
ductile, lighter, resistant towards corrosion and cheaper. Besides that, zincs
are also used as catalysts for many industries chemical reactions like
Frankland-Duppa Reaction in which an oxalate ester(ROCOCOOR) reacts with an
alkyl halide R'X, zinc and hydrochloric acid to form the α-hydroxycarboxylic
esters RR'COHCOOR. There are 2–4 grams of zincs distributed throughout the
human bodies. Most zincs are found in the brain, muscle, bones, kidney, and
liver, with the highest concentrations in the prostates and parts of the eyes.
Semen is particularly rich in zinc. Zincs also play a key role in the prostate
gland function and the growth of reproductive organ. Zincs are transferred and
stored in metallothioneins. In proteins, Zn ions are often coordinated to the
amino acid side chains of aspartic acid, glutamic acid, cysteine and histidine.
In humans, zincs act as ubiquitous biological role by interacting with a wide
range of organic ligands. Zincs also help in the metabolisms of RNAs and DNAs,
signals transduction, regulation of apoptosis ,and genes expressions. Zincs are
also important in the brain functions like learning and memory. In brain zincs
are stored glutamatergic neurons in the form of specific synaptic vesicles. But
excessive of it may lead to neurotoxicity, thus the homeostasis of zincs in
brain are extremely important.
The
first article regarding the biochemistry of zinc which I am discussing here is “Copper,
zinc, and magnesium levels in non-insulin dependent diabetes mellitus”. The
research in this journal was done by Abdul Hamid Zargar, Nissar Ahmad Shah,
Shariq Rashid Masoodi, Bashir Ahmad Laway, Farooq Ahmad Dar, Abdul Rashid Khan,
Fayaz Ahmad Sofi, and Arshad Iqbal Wani.
This
study was designed to find out the
relationships between trace elements, (zinc, copper, magnesium) and
diabetes mellitus. In this study, 83 patients with non-insulin dependent
diabetes mellitus were involved. 40 of them were men and 43 of them were women.
These samples were having the diabetes with the durations between 3.6 to 3.9
years. However, the patients with nephropathy were excluded in this study. A
control group was also been used, this control group was made up of thirty
healthy non-diabetic subjects. All the subjects were subdivided into obese and
non-obese groups. Diabetic subjects were also subdivided into controlled and
un-controlled groups. The controlled patients were made up of those people with
fasting blood glucose and serum fructosamine levels. The serum concentrations
of zinc, copper and magnesium were analysed using a GBC 902 double beam atomic
absorption spectrophotometer.
Age,
sex, duration and control of diabetes patients did not affect the copper, zinc,
or magnesium concentrations. The copper levels of diabetic patients were
seriously elevated (p<0.01) ,while the plasma concentration of zinc and
magnesium were comparable between diabetic and nondiabetic subjects. We
conclude that zinc and magnesium levels are not altered in diabetes mellitus.
Thus it is the copper and not zinc concentration should be the targeted for the
development of drugs for non-insulin dependent diabetes mellitus.
Next,
I am going to discuss on an official journal published by American Academy of
Pediatrics. The title of this journal is “A Meta-analysis of the Effects of
Oral Zinc in the Treatment of Acute and Persistent Diarrhea.” The study in this
journal was conducted and written by Marek Lukacik ,Ronald L. Thomas and Jacob
V. Aranda.
Diarrheas
and zincs deficiencies are considered as two main problems faced by children in
developing countries. These are due to the lacking of clean water and the
problem of starvations. Zincs supplements are usually given by United Nations
to the children in poor developing countries. This is because supplementary
zincs were previously been thought to provide therapeutic benefits in diarrhea.
So the aim of this study was to examine the efficacy and safety of these oral
zincs therapies in the managements of acute or persistent diarrheas.
In
this study, children suffering from acute and persistent diarrhea were used as
samples. There were divided into a manipulation group and control group. The
first group was treated with oral zincs supplements, the second group, which is
the control group, was treated with placebos. The efficacy and safety were
assessed among these two groups of patients. All the results were reported
using a pooled relative risk or a weighted mean difference.
From
the results they obtained, they concluded that oral zincs supplements can help
in the alleviations of acute and persistent diarrheas in children, by reducing
the severity and duration of diarrhea. But the mechanisms behind these actions
remained un-clear to them. Although these zincs supplements do help in the
treatments of acute and persistent diarrheas but they lead to the problems like
vomits and constipations. Basically, the mean durations of acute diarrhea and
persistent diarrhea were significantly reduced for those children treated with
oral zincs supplements. In facts, these treatments were more effective for
those with persistent diarrhea than for those with acute diarrhea. At day 1
(one day after the zincs supplements and placebos were given to respective
groups of patients), the occurrences and severities of diarrheas between zinc
and placebo treated patients do not show any significant difference. It is only
at day 3 that a significant difference been observed. At day 3, the occurrences
of diarrheas in patients treated with oral zincs supplements were significantly
lower than those who were treated with placebos. And also, the improvements
seen in patients with persistent diarrheas were more than those with acute
diarrheas. Vomits experienced by patients with acute diarrheas were also found
to be more severe in those with acute diarrhea (11 cases) but lower in those
with persistent diarrhea (only 4 cases). They also found out that children
given with zinc gluconate vomited more than those given with zinc
sulfate/acetates. In this study, some children actually experienced the
problems of constipations right after their diarrhea had been stopped by oral
zinc therapies.
These
results showed to us that oral zinc supplements benefit those children with
persistent diarrhea than those children with acute diarrhea, and also the side
effects experienced by those with persistent diarrheas were lower than those
with acute diarrheas. Zinc sulfate/acetates can be used to relace zinc
glutamate if the side effect like vomit is to be reduced. With these new
findings in mind the healthcare providers can actually adjust their treatments
choices for children with different types of diarrhea. And whether the results
obtained here can be extrapolated to adults or children of different
backgrounds was still a mist. Further researches and studies are needed before
these extrapolations can be made.
The
last journal I am discussing here which is related to the biochemistry of zinc
is “Zinc-Alpha 2-Glycoprotein Gene Expression in Adipose Tissue Is Related with
Insulin Resistance and Lipolytic.” This study was conducted by Lourdes
Garrido-Sa´nchez and his research team. Zinc-α2 glycoprotein (ZAG)
is a gene which produces Zinc-α2 glycoprotein. This Zinc-α2
glycoprotein has a binding site for zinc. And it needs zinc for its’ function.
Thus its’ activity is directly related to the biochemistry and concentration of
zinc in our body. Zinc-α2 glycoprotein is a metal-complex which will
stimulate the lipid loss of the body by adipocytes and may be involved in the
regulation of adipose tissue metabolism. But their relationship with lipogenic
and lipolytic genes and with insulin resistance (IR) remained unknown. Thus the
study conducted here was to correlate the biochemistry of zinc and the expression
of ZAG with the lipogenic, lipolytic and insulin resistance. There are total of
50 samples involved in this study, 25 of them were made up of non-diabetic
morbidly obese patients, 11 of them made up of low IR patients and 14 of them
made up of high IR patients. The mRNA expression levels of PPARγ, IRS-1,
IRS-2, lipogenic and lipolytic genes as well as ZAG gene in visceral
(VAT) and subcutaneous adipose tissue (SAT) were also quantified. Plasma ZAG
was also analyzed. From the results they obtained, they concluded that patients
with high VAT ZAG expressions are usually those from morbidly obese group.
Besides that, they also found out that those with low IR had a higher VAT ZAG
expression as compared with those with
high IR. In the patients with low IR, the VAT ZAG expression was greater
than that in SAT. ZAG expression correlated between SAT and VAT. VAT ZAG
expression was mainly predicted by insulin, HOMA-IR, plasma adiponectin and
expression of adiponectin and ACSS2. SAT ZAG expression was only
predicted by expression of ATGL.
As a conclusion, we can said that the plasma zinc level and ZAG
level not only correlated to insulin resistance (IR) but they also affect the
metabolisms of lipids in adipose tissues. Thus, the future treatments for
obesity and problems like diabetes should target on the modulation of zinc and
ZAG levels.
After
reading through these reputable journals on CYP450, Metallothioneins, and
Biochemistry of Zincs, I had learnt to appreciate the affords done by these
researchers. I also learnt to become humble as I realized that there are still
a lot of things outside the world that I am still not aware of. The techniques,
methods and findings written in these journals had inspired me a lot especially
in the aspect of drugs developments. After reading through these journals and
articles I had been acknowledged with the current trends in drugs discovery and
also the new treatments approaches, thus I will keep reading these kinds of
journals in the future! Readings journals like this are definitely useful
especially in my career!
REFERENCES
1.
Wikipedia Group. Cytochrome P450 Enzyme.[internet].2010[updated on 2012.Cited on cited on 2012 April 1 ].Available from http://en.wikipedia.org/wiki/Cytochrome_P450.
2. W Steimer1, B Müller1, S Leucht.et.al.Prevalence of
Cytochrome P450 2D6 (CYP2D6) and Serotonin Transporter(5-HTT) Polymorphisms in
depressed Inpatients compared to a Control Group. AACC, San Francisco.Vol.
1.[Journal].2000 July 23[cited on 2012 April 1 ].Vol.1.pp11
3. Lauren N. Bell, PhD, Jean P. Molleston.et.al.Pediatric
Nonalcoholic Fatty Liver Disease and Its Subtypes. Clin
Gastroenterol. Volume 45, Number 9.[Journal] 2011October 9 [cited on 2012 April
1 ]. Volume 45. Number 9.page 801-805.
4. Joanne S. L. Lim, Xiang A. Chen, Onkar Singh.et.al.
Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen
pharmacokinetics in Asian breast cancer patients. British Journal of Clinical
Pharmacology. Volume 71, Number 5.[Journal] 2011October 9 [cited on 2012 April
1 ]. Volume 45. Number 9.page 738-748
5. Wikipedia Group. Metallothionein.[internet].2010[updated on 2012.Cited on cited on 2012 April 1 ].Available from :http://en.wikipedia.org/wiki/Metallothionein
6. IssamEl Ghazi, Bruce L.Martin, and IanM.
Armitage.et.al. New Proteins Found Interacting
with BrainMetallothionein-3 Are Linked to Secretion. SAGE-Hindawi Access to Research International
Journal of Alzheimer’s Disease.Volume 2011.[Journal] 2011 [cited on 2012 April
1 ]. Volume 2011. Page1-6
7. Georges Carrera,
Ph.D., Jose Luis Paternain, Ph.D.et.al. Hepatic Metallothionein in
Patients With Chronic Hepatitis C: Relationship With Severity of Liver Disease
and Response to Treatment. THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98,
No. 5, 2003.Published by Elsevier Inc [Journal] 2003 [cited on 2012 April 1 ]. Vol.
98, No. 5. Page 1143-1147.
8. Halina Milnerowicz, PhD, Monika Jabaonowska, PhD,
and Anna Bizoc, MSc. Change of Zinc, Copper, and
Metallothionein Concentrations and the Copper-Zinc Superoxide Dismutase
Activity in Patients With Pancreatitis. Lippincott Williams &
Wilkins.[Journal] 2011 [cited on 2012 April 1 ]. Volume
00.Number 00 Page2-7.
10. Abdul Hamid Zargar, Nissar Ahmad Shah, Shariq
Rashid Masoodi.et,al.Copper, zinc, and magnesium levels in non-insulin dependent
diabetes mellitus. Postgrad MedJ .[Journal].2000 July 23[cited on 2012 April 1
].1998.vol74.page 665-668.
11. Marek Lukacik, Ronald
L. Thomas and Jacob V. Aranda. A Meta-analysis of the
Effects of Oral Zinc in the Treatment of Acute and Persistent Diarrhea.
American Academy of Pediatric. .[Journal]. 2008 [cited on 2012 April 1 ].2008.volume:121.326-327
13.
Lourdes
Garrido-Sa´nchez. Eduardo Garcı´a-Fuentes.et.al. Zinc-Alpha
2-Glycoprotein Gene Expression in Adipose. Tissue Is Related with Insulin
Resistance and Lipolytic Genes in Morbidly Obese Patients. PLoS
ONE. .[Journal]. 2012 March [cited on 2012
April 1 ].Volume
7. Issue 3 .
