Systematics review

“Mechanisms of curcumin against liver damage induced by organic

compounds”

By :

FITRIANI FAJRI A., S. Farm

1208062113

PROGRAM STUDI PROFESI APOTEKER FAKULTAS FARMASI

UNIVERSITAS AHMAD DAHLAN

YOGYAKARTA

2013
 SCIENTIFIC REVIEW ARTICLE

Mechanisms of curcumin against liver damage induced by organic compounds

Fitriani Fajri A., S. Farm/ 1208062113

ABSTRACT

Background: toxicant can lead to various types of toxic effects on various cell organelles in
the liver, such as fatty liver (steatosis), necrosis, cholestasis, and cirrhosis. Curcumin is a
hydrophobic polyphenol compounds isolated from the plant Curcuma Sp and has various
types of biological activities such as anticancer, antiviral, antioxidant and anti-inflammatory.
Review articles is made to determine how the mechanisms of curcumin against liver damage
induced by organic compounds.

Methods: Data search on PMC and Google Scholar databases using the keywords
hepatoprotector, curcumine, mechanism. Inclusion criteria were taken is a research journal
speak Indonesian and or English, which was published in 2000 - 2012 in the form of study in
vivo and in vitro, in the form of PDF, full text and abstract. Journal which contains the
mechanism of curcumin against liver damage induced by inorganic compounds and
mechanisms that are not associated with liver damage, including in the exclusion criteria.

Results: Many journals that discuss about the mechanisms of curcumin against liver damage
induced by organic compounds in particular ethanol. Most journals have discussed curcumin
isolated from turmeric (Curcuma longa), still lack the journal that addresses the mechanisms
of curcumin isolated from Curcuma xanthorrhiza Roxb.

Conclusion: Curcumin found in plant Curcuma Sp. can improve the liver damage induced by
organic compounds such as ethanol and chloroform. This shows that for further curcumin
could be an alternative treatment for liver damage (cirrhosis of the liver).
INTRODUCTION

Toxicity is a term in toxicology which is defined as the ability of a chemical to cause

harm. This damage depends on the amount of chemical compounds that are absorbed. The
new destruction process occurs in the target organ has heaped considerable amount of a toxic
agent or its metabolites. Furthermore, for most of the toxins, the high concentration in the
body will cause more damage. Concentration of toxins in the body is a function of the
amount of toxins presented, which relates to the speed of absorption and the amount
absorbed, is also related to the distribution, metabolism and excretion of the toxic agent
(Mansur, 2008).

Toxic effects are very varied in nature, target organ, and its mechanism of action.
Generally only affect one or several organs alone. This could be due to more sensitivity of an
organ, or high levels of chemicals and their metabolites in the organ. Toxicity is the inherent
nature of a substance, form and level of toxic manifestations in an organism depends on
various factors such as type of dose and duration of exposure, sex, age, nutritional status,
hormonal, physical factors, environmental and social. In addition, the toxic effect of a
substance can be affected by other chemicals are administered concurrently. Toxic effects can
change for many reasons such as changes in absorption, distribution, and excretion of
chemicals, the increase or reduction biotranformasi, as well as the changes in receptor
sensitivity in target organs (Lu, 1995).

The liver is the largest organ and most complex metabolism in the body. Liver is
involved in the metabolism of nutrients and most of the drug and toxicant. Liver structurally
organized by hepatocytes (liver parenchymal cells) (Lu, 1995). Toxicology of heart by
various be more complicated liver damage and various mechanisms that cause damage. The
liver is often a target organ for several things. Most of the toxicant enters the body through
the gastrointestinal system, after absorbed, toxicant brought porta vein to the liver. The liver
has many bindings. Rate of enzymes that metabolize xenobiotic in the liver is high
(particularly cytochrome P-450). This allows most of the toxicant to be less toxic and more
easily soluble in water, making it easier excreted. But in some cases, the toxicant is activated
so as to induce lesions. Liver lesions are sentrilobuler associated with rates of many
cytochrome P-450 is higher (Zimmerman, 1982). Besides the relatively low rate of
glutathione, compared with rates of glutathione in other parts of the liver, can also give rise to
activate toxicant (Smith et al. 1979).
 Toxicant can lead to various types of toxic effects on various cell organelles in the
liver, such as fatty liver (steatosis), necrosis, cholestasis, and cirrhosis (Lu, 1995). the liver
steatosis was severe lipid containing more than 5%. The mechanism of accumulation of fat in
the liver in general, namely the destruction of the liver triglyceride release into plasma.
Hepatic necrosis is death of hepatocytes. Necrosis is usually acute damage. Several chemicals
have been demonstrated or reported to cause necrosis of the liver (Zimmerman, 1982).
Cholestatic is the type liver injury that usually acute. Some anabolic steroids and
contraceptives in addition taurocholic, chlorpromazine, and erythromycin laktobionat have
been shown to cause cholestasis and hyperbilirubinemia due to blockage of the bile
canaliculi. Cirrhosis is characterized by the presence of collagen septa are scattered in most
the liver. Cirrhosis probably derived from single cells necrosis due to lack of repair
mechanisms that cause increased fibroblastic activity and the formation of scar tissue (Lu,
1995).

Curcumin is a hydrophobic polyphenol compounds, which were isolated from the

plant Curcuma Sp. Curcumin has many kinds of biological activities such as anticancer,
antiviral, antioxidant and anti-inflammatory (Yao et al, 2012). Studies in laboratory animals
suggest that curcumin may reduce oxidative stress and inhibit the activation of NF-kB in the
liver injury (Suchittra Samuhasaneeto et al. 2009). Review articles is made to determine how
the mechanisms of curcumin against the liver damage induced by organic compounds.

METHOD

This article reviews of data obtained from research journals that comes from Pubmed
Center (PMC) and Google Scholar. These data were taken by using a keyword that is
hepatoprotector, curcumine, mechanism. Inclusion criteria were taken is a research journal or
speak Indonesian and English, which was published in 2000-2012. Form which will be
reviewed journal of research in vivo and in vitro, in the form of PDF, full text and abstract.
Journal which contains the mechanism of curcumin against liver damage induced by
inorganic compounds and mechanisms that are not associated with liver damage, including in
the exclusion criteria. Journal obtained and analyzed by looking at the mechanism of action
of curcumin against liver damage induced by organic compounds such as alcohols, CCl4 and
etc.
RESULTS AND DISCUSSION

Result

From the search results with keywords used were obtained research journals that need
to be selected with inclusion and exclusion criteria. Search results using keywords is
presented in table 1.1

Source
No of Keyword Title/year Author Information
database
1 PMC Curcumin, Curcumin Decreased Suchittra The outcome of
hepatitis Oxidative Stress, Samuhasaneeto, curcumine can
Inhibited NF-κB Duangporn Thong- improve liver disease,
Activation, and Ngam, Onanong lower the elevation of
Improved Liver Kulaputana, hepatic MDA, and
Pathology in Ethanol- Doungsamon inhibition of NF-kB
Induced Liver Injury Suyasunanont, and activation.
in Rats/ 2009 Naruemon
Klaikeaw

2 PMC Curcumin, Inhibition by Qun-yan Yao, Bei- Curcumin could

cirrhosis curcumin of multiple li Xu, Ji-yao Wang, significantly attenuate
liver sites of the Hong-chun Liu, chloroform-induced
transforming growth Shun-cai Zhang liver inflammation
factor-beta1 signalling and Chuan-tao Tu and fibrosis by
pathway ameliorates inhibition of TGF-β1 /
the progression of Smad and CTGF
liver fibrosis induced expression.
by carbon tetraklorida
in rats/ 2012
3 PMC Curcumin, Hepatoprotective Suzy M salama, Ethanol extract of
Hepatopro effect of ethanolic Mahmood Ameen Curcuma longa
tector extract of Curcuma Abdulla, Ahmed S induces apoptosis,
longa on AlRashdi, Salmah inhibits proliferation
 thioacetamide induced Ismail, Salim S of hepatocytes but has
liver cirrhosis in rats/ Alkiyumi and no effect on the levels
2013 Shahram of hepatic CTP2E1.
Golbabapour So that cirrhosis of the
liver can be inhibited
by the antioxidant and
anti-inflammatory
activity of ethanol
extract of Curcuma
longa and normal
status can be
maintained.

Discussion

This review aims to determine the mechanism of curcumin against liver damage that
has been induced by organic compounds such as ethanol. The liver is the largest organ and
the most complex metabolism in the body. Liver are involved in the metabolism of nutrients
as well as most of the drug and toxicant. Liver is an important organ of the body to detoxify
chemicals that are not useful / harm the body, including alcohol / ethanol. The process of
detoxification of ethanol in the liver occurs in the reaction process peroxidatif peroksisome
by with the help of peroxisomal catalase enzyme using H2O2 (Thannickal and Fanburg,
2000). According to Chamulitrat in Hernawati’s review article explained that ethanol
metabolism in the liver cells causes increased production of free radicals by various
mechanisms causing oxidative stress that will damage liver tissue. The reaction between
ethanol with H2O2 and other reactive radical species which would produce hydroxyethyl
radical is a strong oxidant. Hydroxyethyl radicals can oxidize lipids and proteins resulting in
liver cell damage liver tissue (Hernawati, 2010). According to Kono in Hernawati’s review
article that the expected source of free radicals are xanthin oxidase and NADPH causes
inhibition of this enzyme may reduce the production of free radicals in rats given ethanol
(Hernawati, 2010).

According to Beckman and Ames in Hernawati’s review article that the alcohol-
induced increase in free radicals also occurs through the mechanism of an enzyme inducer.
Alcohol will induce cytochrome P-450 enzyme that is increased. Cytochrome P-450 enzymes
can increase free radicals directly by forming superoxide radicals, or indirectly through
NADPH (Hernawati, 2010). According to Nanji in Hernawati’s review article that increased
free radicals resulting from the furnishing of alcohol to activate nuclear factor that will
increase the tumor necrosis factor (TNF alpha), which acts against necrosis and inflammation
in the liver. Inhibition of nuclear factor with curcumin was found to protect the liver damage
caused by alcohol (Hernawati, 2010).

Curcumin is one of the active compounds found in the plant Curcuma sp. Compound
curcumin has many benefits one of them in overcoming liver damage. Various studies prove
compound curcumin can improve liver damage by various mechanisms.

Alkoholic Liver disease (ALD) represents a spectrum of clinical illness and

morphological changes that range from fatty liver, hepatic inflammation and necrosis to
progressive fibrosis. many of toxic effects of etanol in liver have been assosiated with its
metabolism. Ethanol oxidation generates toxic products such as acetaldehyde, and reactive
oxygen species result in oxidative stress that initiates apoptosis and cell injury. Hepatic
malondialdehyde (MDA) is assayed by determining the rate of production of acid
tiobarbiturat which is a marker of lipid peroxidation. To counteract oxidative stress, cells
have a variety of antioxidant enzymes including superoxide dismutase (SOD), catalase and
glutathione peroxidase. SOD catalyses the rapid removal of superoxide radicals. NF-kB is a
transcription factor which regulates genes involving in inflammation. Activated by endotoxin,
cytokines and oxidative stress. There are also peroxisome proliferator actived receptors
gamma (PPARγ) is a family of the ligand-activated nuclear transcriptional factors which
regulates cell differentiation, apoptosis, lipid metabolism and inflammation. In the study
revealed curcumin improve heart disease, lower the elevation of hepatic MDA and inhibits
activation of NF-kB (Suchittra et al, 2009).

The process of hepatic fibrosis is driven by a complex network of cytokines,

foremost being transforming growth factor (TGF)-β1 and connective tissue growth factor
(CTGF). TGF-β1 acts through different signalling pathways, the most important being the
cannonical smad pathway. Smad proteins are divided into three functional classes: receptor
regulated, common mediator (Co-Smad4), and inhibitor (Smads 6 and 7). CTGF, also known
as CCN family 2 (CCN2), is induced by TGF-β and is considered a downstream mediator af
the effects of TGF-β on fibroblasts. Finding demonstrate that administration of curcumine
effectively protected rat livers from CCl4-induced liver injury and fibrogenesis. These
beneficial effects of curcumine, delaying the progression of hepatic fibrosis, involved
inhibiting TGF-β1/ smad signalling pathway and decreasing CTGF expression (Qun-yan Yao
et all, 2012).

Thioasetamid (TAA, CH3-C(S)NH3) is a hepatotoxin and hepatocarcinogenic when

administered in the diet of experimental animals, and is widely used as amodel of acute and
chronic liver disease. Briefly, after administration of TAA in diet, it is converted to TAA-S-
oxide (TASO) by hepatic microsomal cytochrome P4502E1 (CYP2E1), then transformed to
toxic thioacetamide-S-dioxide (TASO2). TASO2 damages biomolekules of the liver leading to
cirrhosis. TASO2 is covalently binds to macromolekules of hepatocytes causing DNA
damage, protein oxidation and lipid peroxidation of the cell membrane biomolekules. The
hepatoprotective effects of curcumin might be due to direct antioxidant and free radical
scavenging mechanisms, as well as the ability to indirectly augment glutathione levels,
thereby aiding in hepatic detoxification (Suzy M salama et all, 2013).

In general curcumine can improve damage on the liver that has been exposed with
variation organic compounds such as ethanol, carbon tetrachloride and thioasetamid.
Curcumin mechanisms as antioxidant and or antiinflamasi proved as hepatoprotector.

Conclussion

Curcumine found in plant Curcuma Sp. can improve the liver damage induced by
organic compounds such as ethanol, thioacetamid and chloroform. In the next time,
curcumine could be an alternative treatment for liver damage (cirrhosis of the liver).

Bibliographies

Hernawati. 2010. Overview toxic effects of ethanol on liver cells. FPMIPA Indonesia
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Mansur. , 2008. Toxicology and distribution of toxic agents. http://library.usu.ac.id/
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Qun-yan Yao, Bei-li Xu, Ji-yao Wang, Hong-chun Liu, Shun-cai Zhang and Chuan-tao Tu.
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tetraklorida in rats. BMC Complementary and Alternatif Medicine
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