Journal of Biomaterials and Nanobiotechnology, 2012, 3, 452-461 Published Online October 2012 (
Pharmacogenomics: The Significance of Genetics in the
Metabolism of Natural Medicines
Nancy W. Hanna
College of Pharmacy, California Northstate University, Rancho Cordova, USA.
Received June 13th, 2012; revised July 23rd, 2012; accepted August 15th, 2012
Natural products have been implemented in medicine through use as herbal medications, chemical compound extraction
for prescription medication, or a natural source of food to fight various infections and diseases. Genetics has played a
role in identifying various interactions between existing drugs and side effects. In addition, various food allergies have
been identified with children in recent years, suggesting genetic associations between certain populations carrying spe-
cific genetic alleles. The recent availability of genomic data and our increased understanding of the effects of genetic
variations permit a quantitative examination of the contribution of genetic variation to efficacy or toxicity of com-
pounds derived from natural sources. The identification of target molecules relevant for diseases allows screening for
natural products capable of inhibiting targets which can lead to the development of rational treatment of various dis-
eases including neurobiological disorders, cancer, osteoporosis, and cardiovascular diseases. This allows for more op-
portunities to predict the response of individual patients. Identification of genetic variations that arose as a consequence
of naturally occurring compounds will help identify gene alleles, or protein ligands that can affect the pharmacody-
namic and pharmacokinetics of the natural products in question. In addition, diet modification and precautions to food
products can be identified to help consumers limit or increase certain food intake. Understanding the molecular mecha-
nisms underlying these interactions and their modification by genetic variation is expected to result in the development
of new drugs that optimize individual health. We expect that strategies for individualized therapies will lead to im-
proved results for patients.
Keywords: Pharmacogenomics; Natural Medicine; Polyphenols; Lycopenes; Folic Acid; Tobacco; Vitamin E;
Curcumin; Soy; Vitamin D; Digoxin
1. Introduction
Genomics is now playing a major role in identifying in-
formation from the human body and applying it to cur-
rent drug therapy. It has produced a new era of individu-
alized drug therapy for patients to achieve higher effi-
cacy and safety. Due to the enhanced development of
today’s technologies, the long-term benefits of pharma-
cotherapy management are becoming closer to imple-
ment in clinical practice [1].
It has been recognized through several healthcare
management facilities that individuals respond differ-
ently to medications, and the correlation of the drug
medication to the efficacy has led more pressure on phy-
sicians and pharmacists to apply the concept of personal-
ized medicine into clinical practice [1]. However, this
new direction is only possible with the support of phar-
maceutical industry research to conduct clinical trials on
the pharmacotyping of medications, which can also help
researchers cut on the expenses of medications through
conducting more tailored and smaller clinical trials [1,2].
Tailored clinical trials have also proposed several issues
with misinterpretation of genetic factors, which shows
that highly specific genetic tests are needed to eliminate
any false positives or false negatives in the laboratory
setting [2].
The concept of pharmacotherapy has been influenced
through previous research of associating populations
with respect to their geographical, ethnic, or racial back-
ground in regards to their disease disposition or intelli-
gence. In return, pharmacotherapy research has taken this
association to correlate genetic response to medications
Natural product use has been valued for thousands of
years through cave site engraftments or historical docu-
mentation. The search for new medicinal products has
been extrapolated from plants, animals, and micro-or-
ganisms, with historical evidence suggesting the use and
benefits of natural products [3]. It has led the pharmaceu-
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines 453
tical industry to several plant-derived medications through
modern analytical and structural analysis of plant-based
compounds [3,4]. The discovery of morphine in 1805 by
German pharmacist Fredrich Wilhelm Sertürner (1783-
1841) became the first plant-based medical discovery and
influenced several natural-based medical discoveries [3].
Natural products have offered several advantages to
their use in drug manufacture due to the ease of synthe-
sizing chemical compounds which lowered the cost of
drug production [3]. In addition, their use in society has
been easily targeted through its habitual interaction in
nature, such as bacterial suppression, or natural defense
against herbivores, which led drug discoveries in antim-
icrobials, laxatives, and muscle relaxants [3]. Compara-
tive studies between animals and plants has revealed that
both species use similar signaling molecules and recap-
tors, suggesting that plant chemical compounds have the
ability to bind to human disease to modulate binding and
metabolism [3]. Nearly 50% of the drugs introduced in
the past 20 years have been derived directly or indirectly
from natural products, and several in vitro tests such as
medium pressure solid-liquid extraction (MPSLE), rota-
tion planar extraction (RPE), and thin layer chromatog-
raphy (TLC) are currently available for screening plants
and their properties for drug extrapolation and investiga-
tion [4]. Despite this fact, very little effort has been made
to looking at the influence of pharmacogenetics in the
efficacy and toxicity of natural medicines.
Current research of the pharmacogenomics of natural
products is limited, yet provides a great advancement and
potential for the standard use of genetic screening during
pharmaceutical production of natural products. For natu-
ral products that are in the early stages of drug develop-
ment, more research should be conducted to determine if
gene variants are responsible for the differences in ef-
fects and toxicity profiles between patients. If genetic
variants are responsible for the different responses,
pharmacogenomic tests may be used to determine who
will actually benefit from the drug. In addition, poly-
morphisms in the genes for drug-metabolizing enzymes
and transporters may influence the efficacy of natural
medicines mediated through these pathways.
2. Cancer Therapy
2.1. Tea Polyphenols
Obesity has been regarded as one of the major risk fac-
tors and threats for several disease states including car-
diovascular diseases and cancers. It can lead to the over-
activation of fatty enzymes in the body leading to slow
metabolism and blood clot formation in cardiovascular
health, or enzyme activation in cancer [5]. Fatty acid
synthase (FAS) is an important enzyme in human me-
tabolism, and studies have shown that the expression of
FAS is highly increased in human cancer cells, including
breast, colon, ovary, lung and prostate cancer. The pro-
tein hormone, leptin, plays a major role in regulating
FAS by inhibiting its function in the human body; how-
ever, in some patients, FAS has evolved showing resi-
stant strains to leptin [5]. It has led to the research and
development of leptin-like compounds, known as FAS-
inhibitors, which produce cytotoxic effects similar to
leptin by increasing malonyl-CoA levels in the hypo-
thalamic neuron [5].
Several investigators have looked for natural trends in
obesity and populations, and one has led to the discovery
of lower obesity rates in vegetarian populations such as
Asian populations, where black and green tea-drinking in
highly popular.
Tea polyphenols have shown previous clinical benefit
through antioxidant properties and scavenging effects of
radical oxygen species, which lead to several diseases
including cancers. In order to understand the genetic
background of tea polyphenols and possible contribution
to anticancer properties, chemical compounds have been
extrapolated from both green and black tea to understand
the possible chemical contribution to lower obesity rates.
According to C.-W. Yeh et al., green tea contains six
catechins, (+) catechin (C), ()-epicatechin (EC), ()-epi-
catechin 3-gallate (ECG), ()-epigallocatechin (EGC),
()-epigallocatechin 3-gallate (EGCG) and ()-gallo-
catechin 3-gallate (GCG). While, the black tea polyphe-
nols contained theaflavins such as theaflavin (TF-1), the-
aflavin 3-gallate (TF-2a), theaflavin 3’-gallate (TF-2b)
and theaflavin 3,3’-digallate(TF-3) [5].
In order to understand the possible benefit of tea
polyphenols in cancer prevention, MCF-7 human breast
cancers cells were extracted and cultured with tea ex-
tracts from oolong, black, and green tea. in addition, the
understanding of FAS upregulation in obesity and cancer
has evaluated the contribution of several hormones and
signal pathways involved in the upregulation of FAS
gene expression such as sec hormones, epidermal growth
factors (EGF), insulin, and phosphatidylinositol 3-kinase
(PI3K)/Akt signal pathway [5].
The EGCG polyphenol from green tea and TF-3 from
black tea have directly inhibited the FAS protein in the
human body; in addition, to the suppression of EGF and
insulin-induced FAS protein. Due to the contribution of
PI3K/Akt signal pathway in the upregulation of FAS, an
inhibitor of the signal pathway (Ly294002) was also
evaluated, and showed nearly complete inhibition of FAS
expression [5].
2.2. Tomato Lycopenes
The incidence of cancer is highly influenced by diet. It
has been heavily emphasized that diets full of fruits and
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines
vegetables can decrease the risk of cancer. In addition,
low levels of dietary carotenoids have been associated
with certain types of cancers [6]. Carotenoids are a na-
tural coloration to fruits and vegetables which give them
the yellow, orange, or red pigmentation in the plant tissue
[6]. They belong to the tetraterpene family and with more
than 600 known variants. Of these variants, lycopene has
been identified as a contributory anticancer property,
which gives the red pigmentation in the ripe tomato fruits
(Lycopersicon esculentum) [6].
Lycopene microarray analysis with breast cancer cells
(MCF-7, MDA-MB-231, and MCF-10a) revealed several
genetic pathways implicating apoptosis, cell cycle, and
mitogen-activated protein kinase (MAPK) signaling path-
ways [6]. The apoptosis genes regulated through lyco-
pene revealed involvement in the p53, caspase 8, and
tumor necrosis factor ligand. In addition, several genes
were upregulated in DNA repair, including mutS ho-
molog 6 (MSH6), mutL homolog 1 (MLH1), nonpoly-
posis type 2 (MLH1), RAD50 (MCF-10a), v-fos FBJ
murine osteosarcoma viral oncogene homolog (FOS),
mutS homolog 2 (MSH2), and damage-specific binding
protein (DDB2) (MCF-7) [6,7].
In addition, microarray analysis also revealed that ly-
copene induced MAPK signaling transduction by regu-
lating FOS, mitogen activated signal protein kinase 1
(MAP2K1), Janus kinase 1 (JAK1), v-jun sarcoma virus
17 oncogene homolog (JUN), signal transducer and acti-
vator of transcription 3 (STAT3) in MCF-7; BRCA1-
associated protein 1 (BAP1), Ras association (RaIGDS/
AF-6) domain family 7 (C11ORF13), mitogen activated
protein kinase 14 (MAPK14) in MDA-MB-231; and tu-
mor protein p53 (TP53) and protein kinase, DNA-acti-
vated, catalytic polypeptide (PRKDC) in MCF-10a [6,7].
Insulin-like growth factor 1 (IGF1) plays an important
role in inhibiting endometrial, mammary, and lung can-
cer cell proliferation; however, with the addition of ly-
copene, IGF1 was downregulated in gene expression [6].
In addition, lycopene has shown to have upregulation of
the gene GADD45α, which is involved in DNA damage
repair, cell cycle checkpoint, and regulation of apoptosis
pathways. In addition, BRCA1 has also been shown to be
upregulated by lycopene, and induced beneficial apop-
tosis by activating Bcl-2 and GADD45α, and also have
been shown to have additional benefits in damage repair
and signaling [6].
Microarray analysis has also shown addition activation
of damage repair and signaling pathways such as DDB2,
MLH1 and MSH6, which are also mediated by BRCA1
and lycopene activation [6].
2.3. Vitamin B9 (Folic Acid)
Folate was extrapolated from spinach in 1941 by Mit-
chell et al., and was shown that it plays an important role
in DNA synthesis and methylation [8]. In addition, it acts
as a single carbon donor, which can help in the regulation
of cancer cells, through several mechanisms including
the conversion of homocysteine to methionine and purine
and pyrimidine synthesis [8,9]. It has shown that one of
the folate-binding proteins, the human folate receptor
(hFR), can become over expressed in some cancers such
as leukemia, which made it an attractive candidate for
anticancer therapy [8].
In the absence of folate in the diet, insufficient conver-
sion of deoxyuridine monophosphate (dUMP) to de-
oxythymidine monophosphate (dTMP) can lead to mis-
incorporation of uracil into the DNA strands, which re-
sults in increased double-strand breaks during uracil ex-
cision repair [8]. In addition, activated metabolites of
fluoropyrimidines can also add to the aggregation of
DNA damage and interfere with RNA synthesis. Rapidly
multiplying cells are most susceptible to folate deficiency
in the diet, and studies have revealed that gastrointestinal
and hematopoietic cells are the most effected leading to
liquid and solid cancers such as leukemia and stomach
cancers [8].
Folate analogs have been introduced several years ago,
with the most commonly known drug, methotrexate
(MTX). MTX has been shown to be a very successful
antitumor chemotherapy agent with immunosuppressive
properties to treat leukemia, lymphoma, and other auto-
immune diseases such as rheumatoid arthritis. It works
primarily as an inhibitor for the dihydrofolate reductase
(DHFR) which results in an accumulation of dihydro-
folate (DHF) [8,9].
Recent studies have shown genetic variations of meth-
otrexate in its metabolism through several genetic path-
ways including 5,10-methylenetetrahydrofolate reductase
(MTHFR), thymidine synthesis (TS), dihydrofolate re-
ductase (DHFR), methionine synthase (MS), methionine
synthase reductase (MTRR), cystathionine β-synthase
(CBS), serine hydroxymethyltransferase (SHMT), and
reduced folate carrier (RFC) [8,9].
In-vitro studies have shown that MTHFR heterozygote
carriers CT carried intermediate elevated plasma homo-
cysteine levels as compared to the TT and CC homozy-
gote alleles. This polymorphism has showed to be asso-
ciated with different types of cancers including acute
lymphocytic leukemia, colon cancer, neural tube defects,
and possible cardiovascular disease. These types of dis-
eases have been shown more likely in patients with low
folate intake [8-10]. In addition, TS has been shown to be
associated with double or triple repeats in the African
American population, which resulted in an increased
gene expression and increased levels of tumor tissue
DHFR is the primary target of MTX, and in-vitro
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines 455
studies have shown a population-specific polymorphism
first detected in the Japanese population. The results of
these polymorphisms revealed an increased expression of
DHFR with the homozygous TT genotype of the C829T
gene, when compared to the heterozygote gene, CT, and
the other homozygote allele CC [9,10]. In addition, indi-
viduals with MS deficiency have shown more likelihood
to experience side effects such as hyperhomocysteinemia,
homocystinuria, and megaloblastic anemia. Homocys-
teine levels have been linked to D919G, and in-vitro
studies have revealed that individuals with the DD geno-
type experienced a higher homocysteine level, while the
GG genotype experienced the lowest homocysteine level
MTRR deficiency has lead individuals to suffer a vari-
ety of disorders including deficiency in folate/cobalamin
metabolism. In 1999, it was revealed that a substitution
of methionine for isoleucine at codon 22 of gene A66G
was the reason for the deficiency of the enzyme. In addi-
tion, AA homozygous individuals revealed increased
homocysteine levels over the AG heterozygote, and GG
homozygote allele [9,10].
CBS deficiency results in homocystinuria; however,
even though in-vitro studies revealed that polymorphisms
from the substitution of the C to T allele on the nucleo-
tide 699 and 1080, these polymorphisms acted as silent
mutations [9,10]. Whereas, SHMT polymorphism in the
C1420T allele of cSHMT gene revealed that red blood
cells and folate levels were elevated in a small degree in
individuals with the T allele (TT and TC) as compared to
the CC homozygous alleles. Lastly, RFC polymorphism
shows potential for pharmacogenomic relevance since it
plays a major role in the entry of MTX into the cell;
however, studies have not yet shown its significance
2.4. Tobacco
Tobacco is growth from the plant, Nicotiana tabacum
[11], and has been widely used in cultivating cigarette
products for tobacco smoking. It is estimated that 29% of
the world’s population over the age of 15 smokes, with
harmful effects on the human cells affecting short-term
memory, which in return affects attention [12]. In addi-
tion to memory, tobacco has been associated with nearly
30% of tumors, and involves several sites including lungs,
head, neck, esophagus, stomach, liver, pancreas, bladder,
kidney, and myeloid leukemia [13].
Lung cancer is considered one of the most fatal can-
cers, and the first tumor associated with it involved ciga-
rette smoking.
The tumor size is influenced by many factors such as
the number of cigarettes, age, pattern, type of tobacco,
and several other factors [13]. While nicotine itself is not
a carcinogenic, it leads to addiction and possible facilita-
tion to other carcinogenic mechanisms such as angio-
genesis. Tobacco carcinogens include polycyclic aro-
matic hydrocarbons (PAHs), such as benzo(a)pyrene,
benz(a)anthracene and chrysene, N-nitrosamines, such as
tobacco-specific nitrosamines (TSNA), 4-(methylnitro-
samino)-1-(3-pyridyl)-butanone (NNK), and N-nitro-
sonornicotine (NNN), and lastly, aromatic amines [11-
The metabolism of tobacco is dependent on the cyto-
chrome P450 (CYP) enzymes. TSNA, nicotine, and other
tobacco carcinogens are mainly activated by the CYP2A
enzyme. The human CYP2A enzyme contains three
types, which include the CYP2A6, CYP2A7, and CYP
2A13 [12,13].
CYP2A6 is the main active enzyme and mainly ex-
pressed in the liver, with other expression in other organs
such as the nasal epithelium, trachea, lung and esophagus.
The lung and esophagus have the highest expression of
CYP2A6, with 50-fold and 41-fold, respectively. While
the CYP2A13 is mainly expressed in the nasal epithet-
lium compared with the other organs. However, the ex-
pression of CYP2A6 remains the most active enzyme in
the human body compared to the other enzyme deriva-
tives [11-13].
Nicotine is viewed as a pro-drug, and requires the me-
tabolism of 5’-hydroxylation to convert it to its active
metabolite cotinine. Cotinine can be further metabolized
in the body by trans-3’-hydroxycotinine, which is the
main compound found in urine [12,13]. While, In vi-
tro-studies have correlated CYP2A13 expression in nico-
tine metabolism to cotinine, the expression of CYP2A6
in the main conversion of nicotine to cotinine in the hu-
man liver, which also participates in further converting
cotinine to trans-3’-hydroxycotinine for urinary excretion.
CYP2A6 can be heavily influenced by genetic composi-
tion, diet, and environment, which can lead an individual
to become a CYP2A6 inhibitor or inducer [12].
In addition to nicotine conversion, NNK and NNN
carcinogens have also assisted in the expedition to can-
cerous formation while also depending on the CYP2A
enzyme metabolism pathway. It is understood that NNK
can be metabolized to two metabolites, α-methyl or α-
methylene hydroxylation, depending on the tissue it en-
counters. The expression of the different CYP2A en-
zymes has also influenced the conversion of the carcino-
gens [13]. The α-methyl pathway is metabolized by the
CYP2A6 enzyme pathway, while the α-methylene hy-
droxylation is metabolized through the CYP2B6 and
CYP2A13 enzyme pathway, leading researchers to ac-
knowledge that α-methyl is the main metabolism path-
way for nicotine due to its direct association with
CYP2A6 [13].
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines
NNN can also become metabolized at the 2’- and
5’-hydroxylation pathway, noting that the 5’-hydroxy-
lation is considered the main stream pathway in humans,
which is carried out by the cartelization of the CYP2A6
and CYP2A13 [12].
Genetic factors play an important part in the likelihood
of smoking tobacco. Genetic polymorphisms in the en-
zyme activity of CYP2A6 can influence individuals to
smoke more or less frequently depending on the copies
found in their genetic profile. Individuals who carry extra
copies of the CYP2A6 gene are considered fast metabo-
lized, and are considered to be susceptible to heavier
smoking due to increased nicotine clearance from the
In addition, individuals who carry inactive or reduced
CYP2A6 alleles can benefit, since their metabolism is
heavily slowed down. The inactive alleles are encoded as
CYP2A6*2, CYP2A6*4 and CYP2A6*20, while the re-
duced enzyme activation are encoded as CYP2A6*7,
CYP2A6*10 and CYP2A6*17 [12]. These genetic fac-
tors have been shown to be influenced by ethnicity, as
in-vitro studies have showed that even though Afri-
can-American individuals smoked as much as Euro-
pean-Americans, their serum concentration for nicotine
was nearly 50% and 30% of nicotine and cotinine per
cigarette intake, respectively, which showed that Afri-
can-Americans have a genetic predisposition for lower
nicotine clearance from the body [12,13]. In addition,
Nakajima et al., and showed that Japanese nicotine and
concentrations in the body were higher than African
Americans and European Americans, while J. T. Kwon,
et al. showed the same predisposition with Koreans. These
studies suggest that ethnic background carry a predispo-
sition to the likelihood of heavy smoking according to
their genetic allele [12].
These studies have led to more investigational drug
discovery to make new drugs that target the inhibition of
the CYP2A6 metabolic pathway. It has been observed
through the use of 8-methoxypsoralen, a CYP2A6 in-
hibitor, and it showed that individuals who carried this
gene had a higher nicotine plasma concentration in the
body, which resulted in nearly 24% reduction in the
number of cigarette smoked per day, an 84% increase in
the intervals between each cigarette to the next, and a
25% reduction in the total amount of puffs per day [11-
Methoxsalen (8-methoxypsoralen), a CYP2A6 inhibi-
tor, was introduced into the market suggesting a possible
beneficial affect for individuals consuming this product.
In addition, the drug proposes addition benefits since
CYP2A6 does not have a major role in the body, elimi-
nating any drug interactions or unwanted side effects
2.5. Kampo and the Use of Shikonin
Kampo has been used in Chinese culture as a natural
medical plant by monks. Its use has also been docu-
mented in Japanese emperor’s courts. The chemical
components of the medicinal plant have been used
mainly as a compounded agent with other medicinal
plant, giving it the wide array of use in medicine. The use
of kampo increased further as a supportive agent for
chemotherapy individuals, since it promotes physical
reconditioning and reduces the side effects of chemo-
therapy [14].
A molecular analysis was conducted using different
Chinese medicinal plants, and it was determined that
Shikonin possessed anticancer properties against mRNA
expression. It is commonly known as zicao, and derived
as the dried root of plant species Lithospermum eryth-
rorhizon [15,16]. The microanalysis showed that Shi-
konin several cancer pathways, such as mRNA suppres-
sion, DNA topoisomerase I and II, and bioreductive al-
kylation, increased concentrations of p27 and p53, and
decreased bcl-2 and Bcl-XL leading to apoptosis which
can help target cancer genes [14-16]. In addition, it
showed that the medical plant had effects at the G0/G1
phase of the cancer cell cycle, which induces apoptosis
of cancer genes in the early stage of the cycle. It has also
showed that the use of this herb did not show any side
effects for lung cancer patients treated with zicao [16].
In order to further understand the effects of zicao in
chemotherapy, an in-vitro analysis was conducted by
Yuan Yao, et al. examining its effects on estrogen in
breast cancer patients. The results of the study showed
the benefit of zicao in several anticancer inhibitory
pathways including suppression of ERα-dependent gene
transcription, ERα-positive breast cancer cells further
verifying its beneficial effects as its use in anti-cancer
therapy [16].
3. Cardiovascular Diseases
3.1. Tea Polyphenols
Chemical extracts from green and black tea were ex-
tracted and fed in a prospective clinical trial to examine
the effects of tea polyphenols in anti-obesity effects.
2.5% pulverized green tea leaves were for to rats for 63
weeks, and the results showed that in addition to neutral
effects of tea leaves to the liver and kidney of the rats,
body weight reduction and hypolipidemia was observed.
The LDL-cholesterol, total cholesterol, and triglycerides
were reduced in the treated group compared to the con-
trol group [5].
In addition, in-vitro studies have shown the clinical
benefit of the green tea polyphenol EGCG, which
showed to have a similar mechanism to the effects of
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines 457
leptin, acting as a FAS-inhibitor in the body [5].
3.2. Vitamin E
Cardiovascular diseases have attributed to several com-
plications including diabetes mellitus, hypertension, in-
creased risk of stroke and myocardial infarction, and
even cancer. Diabetes mellitus with cardiovascular dis-
eases increases the burden of patient health through in-
creased free radical oxygen species in the body. Al-
though several clinical trials did not show that additional
benefit of Vitamin E helps patients, it left researchers to
investigate the possible polymorphism in the genetic pro-
file of patients [17].
Cardiovascular disease also leads patients to experi-
ence oxidative stress, which promotes further production
of highly reactive oxygen species (ROS). They contain
unpaired electrons, which can further aggravate the body
through its involvement in intracellular signaling. It can
also result in several chain reactions that cause signifi-
cant damage to the human biological molecules such as
DNA, proteins, carbohydrates, and lipids. ROS has been
directly related to the development of atherosclerosis,
which happens due to attributing the electron particle of
ROS to the low-density lipoprotein (LDL) causing it to
become an oxidized LDL (ox-LDL), which is taken up
by CD36 scavenger receptors in the macrophages leading
its conversion to foam cells [18].
It has been documented that the level of ROS is in-
creased in diabetes mellitus patients, and hyperglycemia
adds to the additional ROS generation. Antioxidant
compounds have been suggested as potential cure for
certain ROS species, while Vitamin E concentrations are
decreased in diabetes mellitus patients [18]. Vitamin E
comes in a synthetic and natural form. The synthetic
form consists of both the D- and L-stereoisomer, while
the naturally occurring Vitamin E only contains the
D-stereoisomer which still contains a high antioxidant
property [18]. The most abundant form of Vitamin E is
the α-tocopherol, and it is most prevalent in naturally
occurring forms of Vitamin E, and acts as an antioxidant
agent against the cells. It was shown that it can react with
peroxyl radicals to form lipid hydroperoxide and the to-
copheroxyl radical, which is a relatively stable and unre-
active with the body’s constituents [18].
One polymorphism that could affect the patient re-
sponse was the haptoglobin (Hp) genetic locus produced
in the liver and binds to free hemoglobin (Hb) released
from the blood. It prevents the Hb from participating in
oxidative injury in the human body in the hepatic site;
however, in extrahepatic sites, it can also serve as a stress
factor for the body, by preventing the release of heme
iron in the body due to stringent binding, which leads to
the formation of the Hb-Hp complex. The complex can-
not be cleared by the liver, and can only rely on the ma-
crophages, which in return, transforms into foam cells
The Hp gene contains several louses including the Hp1
(Hp1-1 allele), which is more prevalent in Western
populations, and the Hp2 gene (Hp2-2 and Hp2-1 alleles),
the later is present only in humans and provides less
beneficial effects of antioxidant protection against Hb
when compared to Hp1 [17]. Hp polymorphism has been
documented as a major determinant for determining the
risk of developing cardiovascular diseases in diabetes
mellitus patients. However, the increased risk of cardio-
vascular disease was most prevalent in patients who pos-
sessed the Hp-2 gene, with the highest risk for individu-
als who carried the Hp2-2 allele [17]. Individuals with
the Hp-2 gene experienced more risk for developing dia-
betic retinopathy, diabetic nephropathy, and atheroscle-
rosis compared to those who carried the Hp-1 gene [18].
Vitamin E supplementation (400 IU per day) was
given to diabetes mellitus patients with Hp1 and Hp2
polymorphisms and investigated for risk of myocardial
infarction and stroke. The Hp2-2 group who received
Vitamin E significantly benefited from the added sup-
plement, and consequently a significant reduction in the
number of cardiovascular events by over 40%. In addi-
tion, Vitamin E supplementation has shown to reduce
atherosclerotic lesion size and progression, platelet adhe-
sion, and protein kinase C activation [18]. In addition,
the use of Vitamin C showed to have a harmful effect on
the genotype, increasing the oxidative activity of the lip-
ids and blocked the activity of Vitamin E to correct HDL
dysfunction [17]
3.3. Curcumin
Curcumin (diferuloylmethane) is the yellowish compo-
nent of curry, which is a popular culinary meal in the
Asian sub- constituent, especially in the Indian culture. It
a polyphenolic compound extracted from the rhizome of
the Curcuma longa L. (family Zingiberaceae) [19]. It has
been studied excessively and showed potential for its use
as an anti-inflammatory, anti-oxidative, anti-vial, and
anti-hypercholesterolemic agent. In several in-vitro stu-
dies, it has been shown to inhibit hepatic stellate cell
(HSC) activation, with induction of the PPARγ and sterol
regulatory gene element binding proteins (SREBPs),
leading to a reduction in the cholesterol [20].
Ox-LDL is the major lipid component leading to hy-
perlipidemia, which predisposes individuals to suffer
from additional cardiovascular complications including
hypertension, stroke, and myocardial infarction. Lipids
are mediated in the body through several mechanisms
and scavenger receptors, including the LOX-1, SR-AI/II,
CD36, and SR-BI [20]. The expression of each scavenger
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines
receptor relies on specific tissues in the body, such as
CD36’s high expression in macrophages, which plays a
major role in LDL cholesterol found in human macro-
phages. LOX-1 is the main receptor signal pathway for
ox-LDL cholesterol, which is found primarily in the hu-
man epithelial cells. It also plays a major role in con-
verting ox-LDL into HSC [20].
LOX-1 is a scavenger receptor, which facilitates the
accumulation of ox-LDL, and stimulates the human cells
to transform macrophages into foam cells increasing the
cholesterol level in the body. In order to further under-
stand the effects of curcumin, HSCs were cultured with
human ox-LDL. Curcumin was shown to suppress the
LOX-1 expression [20].
The main beneficial effect of curcumin was due to its
direct effect on the expression of PPARγ. The activation
of this signal pathway added to an additional inhibition
of the LOX-1 gene expression, through the increased
expression of the canonical Wnt signaling, which medi-
ated the effects of LOX-1 suppression. In addition,
through dose-dependent curcumin, it showed that it can
directly affect the Wnt signaling, and decreased the DNA
binding of Wnt signaling pathways [20].
4. Osteoporosis
4.1. Soy
Estrogen plays a critical role in bone homeostasis. The
receptors of estrogen are expressed in the osteoblasts and
osteoclasts. In osteoclasts, they play a role in inhibiting
interleukin (IL) 1, IL6, IL7, tumor necrosis factor-α, and
the receptor activator of nuclear factor (NF)-κB ligand
[21]. In addition, osteoblasts help promote a longer life-
span by inhibiting their apoptosis. The beneficial effects
of estrogen in bone formation can also be proven by the
increased bone mineral density loss in female patients
after the menopause, since ovarian production of estro-
gen is significantly decreased [21].
Aromatase is involved in the conversion of C-19 an-
drogens into estrogens. It is the last process of estrogen
production, which converts the androstenedione and tes-
tosterone into the C-18 estrogens. It is expressed in the
gonads and plays a critical role in the ovarian synthesis
of estradiol [21]. The aromatase enzyme is also ex-
pressed in several other tissues including fat, placenta,
breast, skin and bone. Estrogen involvement in bone
formation and stability has been associated with its in-
teraction with the osteoblastic lineage and chondrocytes.
Estrogen contains many precursors in the body, with es-
tradiol being the most active compound among the natu-
ral estrogens [21]. The enzyme is found in the endo-
plasmmic reticulum and expressed through the cyto-
chrome P450, primarily through the CYP19A1. Several
polymorphisms have been expressed; the most widely
known polymorphism is the TTTA repeat sequence in
intron 4, which is also linked the TTC insertion/deletion
polymorphism. The TTTA short alleles have been found
to have lower BMD in postmenopausal women [21,22].
Soy has been viewed as a natural estrogen replacement
for postmenopausal women. It contains several phytoes-
trogens, primarily genistein, which shows slowed rate of
bone loss formation through several protein synthesis,
such as protein synthesis in osteoblast-like cells [23].
Dietary soy has been investigated and showed similar
effects of reduced bone density through suppressed bone
turnover. In addition, phytoestrogens in soy have been
found to be endoplasmic reticulum (ER)-β selective, and
bind to it with a higher selectively than the strongest
form of estrogen, estradiol, indicating that soy may exert
its effects in a separate and distinct form than traditional
estrogen [23].
4.2. Vitamin D
The major source of Vitamin D is the human skin. It is
produced through the action of ultraviolet (UV) light on
steroid receptors. It is also found in natural substances
such as dietary food, and can help patients when there is
insufficient UV exposure. It also correlates with the de-
creased dietary calcium and sunlight exposure of elderly,
and highly suggestive of different levels of Vitamin D
depending on the age, skin pigmentation, season and sun
exposure a certain population might experience [24]. It
can be derived from plant substances, with a chemical
composition of Vitamin D2, ergocalciferol, and animal
sources, with a chemical composition of Vitamin D3,
cholecalciferol. It is absorbed in the small intestine in the
presence of bile acid [24].
Despite its name, it is not a true Vitamin, but a
pro-steroid hormone that is metabolized into 23-hydroxy-
chlecalciferol (25OHD), which acts as the major storage
form. The active metabolite of vitamin D, calcitriol (1.25
(OH)2D), is metabolized in the kidney, and it’s the main
hormone responsible for the biological effects of Vitamin
D. when calcitriol binds to the Vitamin D receptor (VDR)
to regulate gene transcription of several target tissues
such as bone, intestine, kidney, and parathyroid glands.
Calcitriol exerts its function differently depending on the
target tissue; in the intestine, calcitriol induces the ex-
pression of calcium to help circulate the dietary calcium
into the circulation. While on the bone, it is thought that
osteoblasts secrete cytokines that stimulate osteoclast
differentiation and cone resorption in response to calci-
triol formation [24].
The VDR gene has been proposed as a possible ex-
planation for increased osteoporosis risk. The gene is
located on the long arm of chromosome 12 and com-
posed of nine exons, with eight transcribing exons that
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines 459
are translated into function CDR proteins. Polymor-
phisms in the restriction enzymes BsmI and ApaI have
been documented, with increased osteocalcin levels in
individuals with the “BA” allele [24,25]. The “bb” geno-
type is characterized by the absence of the restriction site
for BsmI, and it was correlated with the highest BMD
value with the lowest fracture risk, while the “BB” geno-
type was typical of women who are just below the
threshold of osteoporotic fracture risk. In addition, hap-
lotype alleles of the VDR gene associated with fracture
risk has been also associated with decreased body height,
decreased bone size, and lower bending strength at the
femoral neck [24].
It has been shown that BsmI VDR polymorphism and
calcium intake encoding the bb homozygote allele
showed a higher BMD, yet no effect during calcium and
Vitamin D supplementation in comparison to the Bb
genotype, crossing from net loss to net gain when con-
suming approximately 1 g/day. In addition, a study was
conducted in postmenopausal Normal American women,
and it supported that women with the BB genotype
showed decreased calcium absorption when compared to
the bb and Bb genotypes. Given that the B genotype is
more prevalent in the European ancestry, it could partly
explain the responsive differences between studies con-
ducted in Asians and Europeans and their response to
calcium and Vitamin D supplementation [25].
5. Depression
5.1. Soy
Stress and sex hormones play a vital role in elevating
mood. The serotonin (5-HT) is one of the main neuro-
transmitters for mood stabilization, and several environ-
mental factors as well as genetics can affect its level in
the human body. 5-HT is controlled by several neuro-
transmitters and regulatory proteins, mainly tryptophan
hydroxylase (TPH), the committal enzyme in 5-HT syn-
thesis, and the 5-HT reuptake transporter (SERT), which
has been a target for several antidepressant medications
such as the selective serotonin reuptake inhibitors (SSRIs)
Depression has been more common in females, sug-
gesting that the elevated estrogen level from the men
strual phase could be attributing to its elevation. Estrogen
has been an important factor in reducing several diseases
and regulating the menstrual cycle of women; however,
artificial supplementation leaves the patient with un-
wanted side effects. It was suggested that natural sup-
plementation of estrogen such as soy phytoestrogen (SPE)
could benefit female patients since it does not have either
agonist or antagonist activity [26].
SERT has been the main regulatory serotonin protein
transmitter in the body, and any dysfunction can lead to
depression or anxiety disorders, as it was documented
that the SERT levels of patient with major depression was
reduced in the midbrain; however, one month of estrogen
replacement helped the SSRI, citalopram, bind more ef-
fectively and produce better results for patients [26].
In-vitro research have suggested the beneficial effect
of adding soy isoflavone supplements since it antago-
nized the estrogen receptor-α and β-dependent gene ex-
pression in the hypothalamus. They also increased the
choline acetyltransferase mRNA levels and the mRNA
neurotrophic factor in the frontal cortex [26]. It was also
shown that SPE can also increase TPH protein in the
serotonin body similar to that of conjugated equine es-
trogens, which is common estrogen product used for hor-
mone replacement therapy. In addition, males could be-
nefit from the added dietary soy products since phytoes-
trogens was shown to decrease medical basal hypothala-
mus and amygdaloid calcium-binding proteins without
interfering with the androgen metabolizing enzymes [26].
5.2. Curcumin
In addition to the beneficial cardiovascular effects of
curcumin, it was shown that the dietary supplementation
also acts as an inhibitor of the transcription factor AP-1,
a gene expression regulatory factor expressed in lithium
treatment [27]. In addition, it was shown that curcumin
helped elevate the brain levels of serotonin [19,28]. It
was also shown that at doses of 10 - 80 mg/kg, demon-
strated a synergistically enhanced effect of tranylcy-
promine (monoamine oxidase inhibitor), fluoxetine (se-
lective serotonin reuptake inhibitor), bupropion (dopamine
reuptake inhibitor), and venlafaxine (dual reuptake inhi-
bitor of serotonin and norepinephrine) [19]. However,
in-vitro studies have not shown a positive correlation
with curcumin addition to desipramine and imipramine
(tricyclic antidepressant) [19].
Dopamine levels are also considered a critical compo-
nent of antidepressant effects and in-vitro studies have
shown that curcumin also played a role in increasing do-
pamine level through MAO-B enzyme activity. It sug-
gested that curcumin potentiates the same effects as
MAO inhibitors [28]. It was also observed that curcumin
can inhibit both the MAO-A and MAO-B receptors; al-
though higher doses were required to inhibit the MAO-B
receptors. The MAO-A receptors were shown to be in-
hibited by low doses, with higher doses inhibiting the
MAO-B receptors with no effect on the norepinephrine
in the brain [28].
6. Atrial Fibrillation
Digitalis have been used in the early 20th century as a
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Pharmacogenomics: The Significance of Genetics in the Metabolism of Natural Medicines
useful medicinal agent for patients with heart failure, it
was later synthesized into digoxin to treat patients with
atrial fibrillation [29]. MDR1 gene encodes for the ATP-
dependent membrane efflux transport for p-glycoprotein,
and it was shown that MDR1 polymorphisms could af-
fect the pharmacokinetics of digoxin [30,31]. The P-gp
acts as a pump to remove substrates from inside to the
outside of the cell. It is expressed in several human tis-
sues such as the liver, kidney, small and large intestine,
brain, placenta, and adrenal glands [31].
In-vitro studies have been conducted, and it was
shown that homozygous wide-type individuals with the
CC allele are considered to be high expressers for the
P-gp, which requires low digoxin levels, while those who
had the homozygous TT allele with low expressers of the
P-gp, and required higher doses of digoxin for controlled
benefits [30]. It was shown in urinary recovery of pa-
tients who were treated with digoxin that TT > CT > CC
supported previous studies that suggested that individuals
with the TT allele required higher digoxin doses due to
low levels of the intestinal P-gp [31,32]. However, it
should not be the only determinant of the expression
since environmental factors such as diet may explain the
differences between intestinal expressions of the P-gp
gene [31].
In addition, it was observed that the C3435T and
G2677T alleles were found in high frequencies with the
MDR1 polymorphism; however, several in-vitro studies
that found no correlation between C3435T on the MDR1
expression based on several different organs such as the
placenta and duodenal tissues with different ethnic back-
ground including Japanese and Caucasians [31]. Unlike
C3435T allele, the G2677T showed a reduced accumula-
tion of the digoxin levels compared to the wild type,
suggested that there might be an enhanced efflux effect
with G2677T [31].
7. Future Perspectives
It is well recognized that different patients express dif-
ferently to medications according to several factors such
as genetics, environment, and food intake. Genetic vari-
ability between individuals and their response to medica-
tions and food could dramatically affect their response
however, this area of research is relatively new and re-
quires several years to decode the human body genomes
and understand its influence with the environment [31].
There have been several issues with many researchers
and the public view on the use of genetics to treat pa-
tients, judging the freedom, justice, health safety, and
privacy as a few of the main concerns people might face
with the availability of pharmacogenomics [33]. How-
ever, several researchers support the aim behind phar-
macogenomics research emphasizing that the genetic data
of individuals will not be used to discriminate against
individuals since they have full control over knowing
their genetic data [33].
The area of pharmacogenomics is still in its infancy;
however, it shows great potential for to understand the
significance behind the genetics of transporters, allele
polymorphisms, and food interactions to enhance the
wellbeing and knowledge of patients.
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