european journal of biomedical and pharmaceutical sciences

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Bogoriani et al. European Journal of Biomedical and Pharmaceutical Sciences

CORDYLINE TERMINALIS KUNTH LEAVES’S SAPONIN LOWERED

PLASMA CHOLESTEROL AND BILE ACIDS LEVELS BY

INCREASED THE EXCRETION OF FECAL TOTAL BILE ACIDS AND

CHOLESTEROL IN MALE WISTAR RATS

Ni Wayan Bogoriani1*

, Ida Bagus Putra-Manuaba1, Ketut Suastika

2,

I Wayan Wita3

*Chemistry Department, Faculty of Mathemathic and Natural Science, University of

Udayana.

1Chemistry Departement, Faculty of Mathemathic and Natural Science, University of

Udayana, Denpasar, Bali, Indonesia.

2Professor of Medicine, Head, Division of Endocrinology and Metabolism, Department of

Internal Medicine, Faculty of Medicine, Rector Udayana University;

3Departement of Cordiology and Vascular Medicine, Faculty of Medicine; Udayana

University, Denpasar, Bali, Indonesia.

Article Received on 05/08/2015 Article Revised on 30/08/2015 Article Accepted on 21/09/2015

ABSTRACT

Saponins in the suspect can inhibit cholesterol absorption directly and

indirectly in the gut so it can reduce plasma total cholesterol and bile

acids, the various mechanisms that are still unclear. The purpose of this

study is to prove that saponin intake of Cordyline terminalis kunth

leaf, can inhibit cholesterol absorption directly and indirectly, thus

lowering plasma cholesterol and total bile acids, by increasing the

excretion total cholesterol and bile acids of feces. The study design

was a randomized post-test only control group design, conducted in Wistar rats. Twenty-five

rats were divided into four groups; Control, treatment 1, treatment 2, and treatment 3, each of

6 rats. The control group was given only the standard diet, treatment 1 was given high-

cholesterol foods, treatment 2 was given high-cholesterol foods and Cordyline teminalis

Kunth leaf saponin 30 mg / day, and treatment 3 was given high-cholesterol foods and

gemfibrozil 30 mg / day. After treatment 30 days and the rats were fasted 18 hours, blood

European Journal of Biomedical AND

Pharmaceutical sciences http://www.ejbps.com

ISSN 2349-8870

Volume: 2

Issue: 5

122-134

Year: 2015

Research Article ejbps, 2015, Volume 2, Issue 5, 122-134. SJIF Impact Factor 2.062

*Correspondence for

Author

Ni Wayan Bogoriani

Chemistry Department,

Faculty of Mathemathic and

Natural Science,

University of Udayana.

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samples were taken and plasma separated for examination of cholesterol, and bile acids.

Three days last treatment the rats feces were collected for examination of total cholesterol

and total bile acids. The results showed an increase in total cholesterol, LDL cholesterol,

triglycerides, ratio of total cholesterol / HDL and a decrease in HDL cholesterol, and

excretion fecal total cholesterol, total bile acids were significantly (p <0.05). In treatments 2

happen otherwise.

Based on the results of this study concluded that the intake of saponins Cordyline terminalis

Kunth leaves can inhibit the absorption of cholesterol directly and indirectly in the intestine,

thus lowering plasma cholesterol and bile acids by increasing the excretion of fecal total

cholesterol and total bile acids.

KEYWORDS: saponins, total bile acids, total cholesterol, foods high in cholesterol.

INTRODUCTION

Saponins are natural detergents that have surface active properties, in which the molecular

structure consists of a steroid or triterpene aglycone called sapogenin and glycon that contain

one or more sugar side chains (Osbourn, 2003; Guclu-Ustundag and Mazza, 2007; Vincken,

et al., 2007).

Saponin derived from the Latin word 'sapo' which shall mean containing stable foam when

dissolved in water. The ability of saponins foam is caused by a combination of hydrophobic

sapogenin (fat soluble) and hydrophilic part of sugar side chains (soluble in water)

(Naoumkina, et al., 2010). Saponins with their detergents properties can affect substan fat-

soluble in digestion, include the formation of a mixed micelles containing bile salts, fatty

acids, diglycerides and fat-soluble vitamins as well as saponins are capable of forming

complexes with metals such as Fe, Mg, Zn, and Ca (Southon, et al. 1988; Cheeke, 2001).

Saponin acts as an emulsifier and can stabilize the interface of oil / water and also has the

ability to dissolve monoglycerides. Based on these activities is believed that saponins able to

emulsify fats (Cheeke, 2001).

Family Liliaceae nown as one of the families that re very rich in saponins. Garlic also

includes the family Liliaceae containing steroidal saponins (Matsuura, 2001). Plants

Cordyline terminalis Kunth including Liliaceae family which contains saponins. Based on the

research results that the Cordyline terminalis leaves contain steroidal saponins but the

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biological activity of the test animals have not been performed (Bogoriani, 2001; Bogoriani,

2008).

Some researchers reported that the saponin from other plants such as garlic steroid glycosides

(Matsuura, 2001), and chloragin of Chlorophytum nimonii (Lakshmi, et al., 2012) and also

from the alfalfa triterpene glycosides of Medicago sativa L. (Khaleel, et al. , 2005)

soyasaponins (Sun-Ok Lee, et al., 2005), Quillaja saponaria (Cheeke, 2001), and ginseng (Ha

and Kim, 1984) have activity as hipocholesterolimea which can inhibit cholesterol absorption

and lowers plasma cholesterol concentrations that have been tested in animals and humans

(Kim, et al., 2003; Zhao, et al., 2005; Afrose, et al., 2010;). However, the mechanisms

responsible for these activities is not clear. Saponins could be expected to prevent formation

of micelles with cholesterol during digestion in the small intestine, thus reducing the

availability of cholesterol for absorption into enterocytes. Saponins are also thought to inhibit

the absorption of cholesterol from micelles and inhibits the reabsorption of bile acid and

cholesterol synthesis due to the interaction of saponins with bile acids to form large mixed

micelles are not soluble so it can not be absorbed by intestines and is excreted through the

feces (Zhao, et al., 2005; Lee Sun-Ok, et al., 2005). Inhibition of reabsorption of bile acids

from the intestine stimulate the metabolism of cholesterol in the liver then converts it into

bile acids (Jenkins and Atwal, 1994; Shin, et al., 2004; Han, et al., 2000). Inhibition of

cholesterol absorption in the intestine is also suspected due to the saponin compounds form

complexes with cholesterol, but its mechanism of action is unclear.

MATERIALS AND METHODS

Diet

Saponin isolated from the leaves of Cordyline terminalis Kunth were grown in Tampak

Siring Bali. Saponin extracted by maceration and precipitation and then analyzed by high-

performance liquid chromatography (HPLC; Bogoriani, 2001; Bogoriani, 2008).

Saponin dose was given 30 mg / day. Diet control as standard food for rats is CP 551 has the

composition of 13% water content; protein from 18.50 to 20.50%; 4% fat; fiber 6%; 8% ash;

0.90% calcium and 0.70% phosphorus. Foods high in cholesterol are the standard diet (60%)

and duck egg yolk (40%).

Animal

White male Wistar rats as research protocol was taken from laboratory Center Study of

Animal Diseases (CSAD) Faculty of Veterinary Medicine, University of Udayana. Twenty-

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four Wistar rats, 11-12 weeks old and weight 150-200 g were divided into 4 groups, a control

group, three treatment groups. Treatment-1 group was treated rats fed high-cholesterol only,

treatment-2 group was treated rats fed a high cholesterol and saponins 30 mg/day. treatment-

3 group of rats was fed a high cholesterol and gemfibrozil 30 mg/day, each group of 6 rats.

Rats from each group individually caged at room temperature, with a 12:12 hours light:dark

cycle. Rats were treated for 30 days and a free drink ad libitum. After 30 days of treatment

the rats were fasted to draw all the food and drinks for 18 hours. Blood was taken via the

orbital sinus, accommodated in blood tubes containing EDTA solution and then centrifuged

at 5000 g for 15 min at 4 ° C to obtain plasma then frozen until analysis.

Analysis of Plasma Lipids and Total Bile Acids

Determination of plasma total cholesterol CHOD-PAP method by E. Merck. CHOD-PAP

method is an enzymatic-colorimetric test is highly specific for the measurement of the area of

light that can be seen by the eye, and can be distinguished from the others because of the high

fleksibelitasnya. Total cholesterol is calculated as: absorbance of sample divided by the

absorbance of standard cholesterol (0.240) multiplied by constant of the standard cholesterol

(200mg/dl).

The principle of HDL analysis according to Human (1980), namely the provision of

phosphotongstic acid and magnesium ions in the sample so that chylomicrons, VLDL and

LDL will settle. HDL levels calculated with the way the sample absorbance multiplied by

318 (mg / dl).

Plasma LDL cholesterol checks were done by reducing total cholesterol with VLDL and

HDL, VLDL whereas calculations performed using triglycerides, VLDL which is equal to

one-fifth (1/5) triglycerides.

Triglycerides examination conducted by the GPO-PAP method. Triglycerides are determined

after enzymatic hydrolysis with lipase. Quinoneimin indicator formed from hydrogen

peroxide, 4-aminoantipirin and 4-chlorophenol under the catalytic influence of peroxide.

Triglyceride levels calculated as follows: sample absorbance divided by the standard

absorbance triglycerides (0.145) multiplied by a constant of triglycerides (200mg/dl).

Examination of the total plasma bile acids done with the kit rat total bile acids (cristal chem.

Inc. USA) in units of μmol / L with a spectrophotometric method. Rat total bile acids kit is

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based on enzymatic technology of 3-α-hydroxy steroid dehydrogenase. The presence of

NAD, bile acids are converted into 3-keto steroids and NADH. The formation of NADH

reacts with blu nitrotetrazolium (NBT) to form color. Color formation was monitored by

measuring the absorbance at 540 nm and direct measurement of rat plasma concentration of

bile acids.

Analysis of total cholesterol and fecal total bile acid

Three days or 72 hours end of the study period. The number of fecal total cholesterol was

measured by spectrophotometry 30 IKM. Two grams of feces was extracted with hexane.

Extracted while shaken and heated with a water bath. Pipetted 0.3 ml of sample and standard

solutions. Then heated in a water bath at 80 ° C for 5 min and then stored in a 105oC oven for

30 minutes. Cool at room temperature and add 4 ml of acetic anhydride, glacial acetic acid

and concentrated sulfuric acid, shaken and allowed to stand 35 minutes, then read on a

spectrophotometer at a wavelength of 630.

Examination of fecal bile acids done by weighing one gram of feces then macerated in

methanol: n-butanol 1:2 for 24 hours and then filtered. Take 1 g aliquots enter into a 50 ml

tube and added 300 mL 1μg/100 mL cholic acid as an internal standard, and then added a

solution of sodium borohydride and shaken for 1 hour to reduce the 3-keto-BAS. Weigh the

body weight of rats before and after the three-day gathering. For saponification BAs add 500

mL 2 N HCl and 2 ml of 10 N NaOH, after the process is filtered. Pipette 20 mL of sample

and plus Cristal Chem Rat Total bile Acids Kit for measurement of total fecal bile acids with

a spectrophotometer.

Statistical Analysis

Statistical analysis was performed with the statistical analysis system. Values are expressed

as mean ± SD. Results were analyzed by one-way ANOVA, and differences between

treatments were determined by a least-significant-difference test (LSD). Alpa 0.05 is used to

determine statistically significant differences.

RESULTS AND DISCUSSION

RESULT

The initial data (control) and after feeding with high cholesterol diet (HC), HC plus saponin

(HC+SP) and HC plus gemfibrozil (HC+GB) of plasma TC, LDL-C, HDL-C, TG, TC/HDL-

C ratio and bile acid and fecal cholesterol and bile acid can be seen in Table 1 and Figure 1.

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The levels of plasma TC (157.83±9.11 vs. 64.83±8.13 mg/dl, p<0.05), LDL-C (95.53±4.27),

TG (169.67±4.72), TC/HDL-C ratio (5.48±0.34) were higher significantly; the levels of

HDL-C (28.87±1.05) was lower significantly; and no any difference of levels of bile acid in

Wistar rat after feeding with high cholesterol compared to control group. Saponin actually

could lower and reversed close to control group of the levels of plasma TC, LDL-C, TG,

TC/HDL-C ratio and bile acid, and increased the levels of HDL-C in Wistar rat after feeding

by high cholesterol. Saponin decreased significantly levels of plasma TC (79.83±9.11 vs.

157.83±9.11 mg/dl, p<0.05), LDL-C (25.57±6.40), TG (36.00±5.55), bile acid (25.10±0.34)

and TC/HDL-C ratio (1.69±0.19); and increased significantly the levels of HDL-C

(47.50±4.63) in Wistar rat feed high-cholesterol compared to without saponin. The effects of

gembfibrozil, well known an active drug for lowering levels of trygliceride and increasing

HDL-C levels, as comparison in the study could be noted also in Table 1 and Figure 1.

The levels of fecal cholesterol (212.82±59.84) vs. 576.95±115.33 mg/kg, p<0.05, and bile

acid (3.75±0.38) vs. 18.65±0.76 were higher significantly in Wistar rat after feeding with

high-cholesterol compared to control group. Saponin increased significantly levels of fecal

cholesterol (1401.29±168.38) and bile acid (34.31±0.88) in Wistar rat feed high-cholesterol

compared to without saponin.

Table1. Plasma TC, LDL-C, HDL-C, TG, TC/HDL-C ratio, and bile acids, and fecal

cholesterol and bile acid in control, HC, HC+SP, and HC+GB in Wistar rats

Group Control HC HC+SP HC + GB

Plasma

TC (mg/dl)

LDL-C (mg/dl)

HDL-C (mg/dl)

TG (mg/dl)

TC/HDL-C ratio

Bile acid (μmol/L)

64.83±8.13

13.67±7.07

42.27±4.76

52.67±1.86

1.53±0.11

45.79±0.69

157.83±9,11a

95.53±4.27a

28.87±1.05a

169.67±4.72a

5.48±0.34a

46.23±0.84

79.83±9.11a.b

25.57±6.40a.b

47.50±4.63a.b

36.00±5.55a.b

1.69±0.19a.b

25.10±0.34a.b

105.33±5.43a.b

38.77±3.12a.b

58.07±3.97a.b

42.33±6.68a.b

1.82±0.74a.b

47.17±1.91a

Fecal

Cholesterol

(mg/Kg)

Bile acids

(μmol/day/100 g

BW).

576.95±115.33a

18.65±0.76a

212.82±59.84a

3.75±0.38a

1401.29±168.38a.b

34.31±0.88a.b

1151.99±208.52a.b

26.42±1.18a.b

TC, total cholesterol; TG, triglyceride; BW, body weight; HC, wistar rats feed with high

cholesterol; SP, saponin; GB, gemfibrozil. aRepresents significant difference from control at

p < 0.05;

bRepresents significant difference from high cholesterol at p < 0.05.

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64.83

157.83

79.83

105.33

Control HC HC + SP HC + GB

Pla

sma

To

tal

Ch

ole

ster

ol

(mg/d

l)

45.79 46.23

25.1

47.17


Pla

sma

Bil

e A

cids

(µm

ol/

L)

576.95

212.82

1401.29

1151.99


Fec

al C

ho

lest

ero

l

(mg

/kg)

18.65

3.75

34.31

26.42

Control HC HC + SP HC + GB F

ecal

Bil

e A

cid

(µm

ol/

day

/10

0 g

bw

)

A

D

B

C

Figure1. Levels ofplasma total cholesterol (A), plasma bile acid (B), fecal cholesterol (C),

and fecal bile acid among control and treated groups.

HC, Wistar rats feed with high-cholesterol; SP, saponin; GB, gemfibrozil.

DISCUSSION

In this study, an increase that was significant (p <0.05) mean total cholesterol, LDL

cholesterol, TG and the ratio of total cholesterol / HDL cholesterol and a significant decrease

(p <0.05) mean plasma HDL cholesterol blood wistar rats were given a high-cholesterol diet

(treatment 1), compared to control rats. Besides cholesterol comes from the food consumed,

can also be synthesized by the body itself so that although the control rats not given feed

containing cholesterol, but still containing blood plasma cholesterol.

The increase in total cholesterol, LDL cholesterol, TG, ratio of total cholesterol / HDL

cholesterol (above 4) and a decrease in HDL cholesterol is a sign of the potential occurrence

of dyslipidemia that encourage the formation of atherosclerosis is a risk factor for coronary

heart disease (Bhat, et al., 2003; Khaleel, et al., 2005). Dyslipidemia is an abnormal

lipoprotein metabolism that lead to atherosclerosis. Atherosclerosis is a condition in which an

artery wall thickens as a result of the accumulation of fatty materials such as cholesterol and

become one of the risk factors for cardiovascular disease (Charlton-Menys and Durrengton,

2006). The results are consistent with studies in rats given a high-cholesterol diet there was

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an increase in total cholesterol, LDL cholesterol, TG and HDL cholesterol decrease

significantly (p <0.01) (Lakshmi, et al., 2012).

The increase in total cholesterol and LDL cholesterol also occurred in studies with rabbits fed

a high cholesterol 28 days (Khaleel, et al., 2005). The increase in total cholesterol, LDL

cholesterol and decrease HDL cholesterol in the blood serum of laying hens were given a

high-cholesterol diet for 60 days also occur with significant (p <0.05) (Afrose, et al., 2010).

In the test rats given high-cholesterol foods and Cordyline terminalis leaf saponin 30 mg / kg

(treatment 2) a decrease in total cholesterol, LDL cholesterol, TG, ratio of total cholesterol /

HDL cholesterol and total bile acids and increased plasma HDL were significantly (p <0.05)

compared to rats given high-cholesterol diet (treatment 1). The results of this study are

supported by the results of the study reported by Al-Matubsi, et al., 2011, that diosgenin

saponins can lower total cholesterol, LDL cholesterol and increasing HDL cholesterol with a

very significant difference (p <0.01). Karaya saponin can lower total cholesterol, LDL

cholesterol and increase HDL cholesterol blood serum of laying hens (Afrose, et al., 2010).

Steroidal saponins from Chlorophytum nimonii also can lower total cholesterol, LDL

cholesterol, TG and raising HDL cholesterol with a highly significant (p <0.01) (Lakshmi, et

al., 2012). Soyasaponin, alfalfa saponins and saponin platycodin also shown to reduce total

cholesterol, LDL cholesterol, TG and the ratio of total cholesterol / HDL cholesterol with a

significant (p <005) (Khaleel, et al., 2005: Sun-Ok Lee, et al., 2005 ; Zhao, et al., 2005).

Intake of Cordyline terminalis leaf saponins were able to reduce total cholesterol, LDL

cholesterol, TG, total bile acids and the ratio of total cholesterol / HDL cholesterol and

increasing HDL cholesterol with a significant difference (p <0.05) compared with treatment 1

(HC). From the results of these studies indicate that saponins of the Cordyline terminalis

leaves have biological activity as anticholesterolemia that can prevent the occurrence of

atherosclerosis which is one of the risk factors for coronary heart disease.

Based on the literature, saponin is a plant glycosides that has amphiphilic properties and

surface active agents. Biological activity is determined by its chemical structure which will

determine the polarity, hydrophobicity, and acidity of the compound. Biological activity of

saponins increased with increasing number of sugar side chains (number of polar groups) are

bound to their aglycone or sapogenin. The strength of the sugar chains also affect the

biological activity of both triterpene saponins and steroidal saponins with a single sugar chain

is more active than the two sugar chains. Stereochemistry of the terminal sugar chain and the

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steroid nucleus is very important to determine the overall activity of the saponin molecule as

it affects the overall conformation of saponins. In general, the cluster aglycone and glycon of

saponins plays an important role in its biological activity as the polar part. Cholesterol, bile

acids, the OH group, the steroid core, the C = C group of saponins interact to form aggregates

such as micelles and form insoluble complexes (Siswandono and Soekardjo, B., 1995; Abid

Ali Khan, et al., 2012).

Structure of Cordyline terminalis leaf saponins have a single sugar chain and consists of three

sugars (2 L-ramnosa and 1 D-fukosa) are bound to their aglycone with each molecular weight

866 g / mol and 868 g / mol (Bogoriani, 2001; Bogoriani, 2008) so the ability to lower plasma

cholesterol in rat blood is higher than gemfibrozil. Based on the data generated in the study

showed that the ability of Cordyline terminalis leaf saponins to bind cholesterol greater than

gemfibrozil with a significant difference (p <0.05). Interaction of the saponins with

cholesterol and bile acids is thought to involve hydrogen bonding (OH group), hydrophobic

bonding or van der Waals bonds (the steroid nucleus) and electrostatic bonds (C = C) so as to

allow the formation of complex stability is quite large and insoluble or formed large mixed

micelle thus causing the barrier to the absorption of cholesterol through NPC1L1 in intestinal

enterocytes. Saponins including compounds having high molecular weight and then interact

with cholesterol and bile acids so that the molecule a large increase resulting in the intestinal

absorption barriers that cause a decrease in plasma cholesterol and bile acids, which are then

excreted into the feces more thereby increasing the concentration of feces cholesterol and bile

acids.

Some researchers reported that saponins with cholesterol in the gut, not absorbed as to form

an insoluble complex compounds, so that it can directly reduce cholesterol into the body by

NPC1L1. Barriers directly from cholesterol absorption of saponins may cause not only

prevent the absorption of cholesterol from the proportion of cholesterol high food, but also

proportion of cholesterol a high carried from bile and mucosal cell desquamation

(Hostettmann and Marston, 1995; Shin, et al., 2004; Lin, et al., 2005: Sun-Ok Lee, et al.,

2005).

In this study also found that the Cordyline terminalis leaves saponin intake can lower plasma

total bile acids with significant differences (p <0.05) compared with the control and treatment

1 (HC). Some researchers reported that the saponin to form micelles with bile acids, resulting

in the ability of bile acids to form micelles with reduced fatty acid, saponin is suspected bile

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acid sequestrants (Cheeke, 2001), which is supported by the observation Oakenfull and

Fenwick, (1990) that the saponins are capable of binding bile acids in vitro. Based on these

results, saponins of Cordyline terminalis leave possibility of forming micelles great with bile

acids, thereby blocking or inhibiting the re-absorption of bile acids in the enterohepatic

circulation by the apical sodium codependent bile acid transporter (ASBT) or ileal Na + / bile

acid cotransporter (Ibat), so causes a decrease in total plasma bile acids directly and decrease

plasma cholesterol indirectly and an increase in bile acid excretion via the feces. Inhibition of

bile acid uptake by inhibiting ASBT is a target to increase liver bile acid synthesis and

reduces plasma LDL cholesterol. Barriers to uptake of bile acids in the enterohepatic

circulation by ASBT can reduce the risk of atherosclerosis (Bhat, et al., 2003). Apical

Sodium Bile Acid Transporter codependent (ASBT) is an important component that mediates

the enterohepatic circulation of bile acid re-absorption in the terminal ileum (Sheneider,

2001). Specific inhibition of ASBT protein will block the re-absorption of bile acids in the

terminal ileum and stimulate its excretion via the faeces, thus reducing the amount of bile

acids returning to the liver (Bhat, et al., 2003).

CONCLUSION

Based on the above results and discussion of a conclusion can be drawn as follows:

1. Intake andong leaves saponin lowered blood plasma total cholesterol of Wistar rats were

given a high-cholesterol diets.

2. Intake andong leaves saponin lowered blood plasma bile acids of Wistar rats were given a

high-cholesterol diets.

3. Intake andong leaves saponin increased the excretion of feces total cholesterol of Wistar

rats were given a high cholesterol diets.

4. Intake andong leaves saponin increased the excretion of feces total bile acids of Wistar

rats were given a high-cholesterol diets.

5. Intake andong leaves saponin can reduce blood plasma cholesterol of Wistar rats in two

ways: by inhibiting the absorption of cholesterol and bile acids in the intestine thereby

increasing the excretion of cholesterol and fecal bile acids.

ACKNOWLEDGEMENT

The study, as part of the Dissertation, was supported by the Directorate General of High

Educations, Republic of Indonesia. The author would like to thank all who have gives

assistance during the study.

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