MODULATING EFFECTS OF CURCUMA LONGA (TURMERIC) AND

www.wjpr.net Vol 7, Issue 9, 2018.

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Karuna et al. World Journal of Pharmaceutical Research

MODULATING EFFECTS OF CURCUMA LONGA (TURMERIC) AND

PIPER NIGRUM (BLACK PEPPER) EXTRACTS AGAINST

ADRIAMYCIN INDUCED GENOTOXICITY IN SWISS ALBINO MICE

J. Karuna Kumari* and K. Rudrama Devi

Department of Zoology, University College of Science, Osmania University, Hyderabad-

500007, Telangana, India.

ABSTRACT

In the present research, studies were carried out to examine the

modulating effects of crude Curcuma longa rhizome extract (CRE)

and Piper nigrum fruit extract (PFE) against Adriamycin (ADR)

induced genotoxicity in germ cells of mice using Sperm Morphology

Assay conducting two experiments. Three different doses of Curcuma

longa rhizome extract and Piper nigrum fruit extract (CRE+PFE)

150+200, 250+300 & 350+400mg/kg body weight along with16mg/kg

Bwt Adriamycin were taken for study based on therapeutic

concentration. In first experiment the antigenotoxic effects of

CRE+PFE were studied and in the second test one group of animals

were treated with Adriamycin alone and animals were primed with

CRE+PFE extracts prior to adriamycin treatment. Control animals were fed only with

physiological saline. All the exposed and control animals were sacrificed on last day of fifth

week and cauda epididymis was dissected out, smear was made and stained with Eosin, slides

were prepared and screened for the presence sperm abnormalities. The results were found to

be insignificant, where CRE+PFE proved to be antigenotoxic in treated animals. A significant

increase in the percentage of abnormal sperms were noted when treated with Adriamycin

alone and the cells showed inhibition in the percentage of abnormal sperms when animals

were primed with CRE+PFE prior to adriamycin treatment. The present study reveals that the

CRE+PFE to be antimutagenic and shows modulating effects against the adriamycin induced

genotoxicity in germ cells of mice. Hence Curcuma longa + Piper nigrum supplementation is

safer in chemotherapeutic strategy.

World Journal of Pharmaceutical Research SJIF Impact Factor 8.074

Volume 7, Issue 9, 1839-1854. Research Article ISSN 2277– 7105

Article Received on

18 March 2018,

Revised on 09 April 2018,

Accepted on 30 April 2018,

DOI: 10.20959/wjpr20189-12244

8533

*Corresponding Author

J. Karuna Kumari

Department of Zoology,

University College of

Science, Osmania

University, Hyderabad-

500007, Telangana, India.


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KEYWORDS: Curcuma longa,Piper nigrum, genotoxicity, Adriamycin, Swiss albino mice

INTRODUCTION

Toxicity is the level to which a chemical substance or a particular mixture of substances can

harm an organism. Antineoplastic drugs are medicines that are used to treat some forms of

cancer. Most drugs on the market are designed to kill only a specific type of bacteria or virus,

but antineoplastic drugs have to target a wide range of cells over sometimes multiple body

systems. As a result, anti-cancer drugs often harm healthy cells in an attempt to kill the

cancer cells. Antineoplastic drugs are very good at killing their targeted cells, but a lot of

other healthy cells tend to end up as collateral damage. This lack of specificity is what causes

antineoplastic drugs to have so many potential side effects.

Adriamycin is an anti-cancer chemotherapy drug and derived by chemical semisynthesis

from a bacterial species.[1]

It is an anthracycline antibiotic closely related to the natural

product daunomycin. This medication is classified as an "anthracycline antiobiotic." Its

generic name is Doxorubicin and other brand name is Rubex. It is also available in liposome-

encapsulated forms as Doxil (pegylated form), Myocet (nonpegylated form), and also known

as hydroxydaunorubicin and hydroxydaunomycin and other trade names in India are Dobixin,

Adrim, Doxobin, Doxorubicin(Adriamycin)etc.

Chemoprevention is the attempt to prevent cancer from developing by using substances that

interfere in the process of carcinogenesis. Chemoprevention uses natural products from foods

or synthetic preparations. Because chemoprevention is used long term, it must be non-toxic,

effective, easy to administer and inexpensive. Few specific agents are currently advised for

widespread clinical use since clinical trials that last up to 15 years are still ongoing. Strategies

for chemoprevention change often based on clinical trial results and scientific discoveries.

Dietary factors and lifestyle changes are important areas in chemoprevention. It is estimated

that through dietary improvements there could be a 50% reduction in colon and rectal

cancers, a 25% reduction in breast cancer and a 15% reductions each in prostate, endometrial

and gallbladder cancers. Cancers of the stomach, esophagus, pancreas, ovaries, liver, lung,

and bladder also may be affected by dietary factors. However, these improvements probably

should come from the diet rather than from dietary supplements.[2]

Dietary spices have been traditionally used to increase the flavor of food and as medicinal

tools for the treatment of disease.[3,4,5]

In literature, several studies have established there is


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inverse relationship between diet high in plant foods (spices) and risk for disease.[6,7]

Epidemiological data supported the health benefits associated with intake of dietary spices

are naturally rich source of phytochemicals including low molecular weight polyphenolics,

flavonoids, carotenoids, anthocyanins. Many spices contain high molecular weight

polysaccharides which may have positive effect on human health.[8,9]

Ayurveda or Ayurvedic medicine is a system of Hindu traditional medicine, is native to the

Indian subcontinent, and is a form of alternative medicine.Conventional medicine is

spreading more especially in urban areas around 70% of Indian population in rural areas still

use of medicinal plants to achieve their important healthcare needs. The use of plants is as old

as history itself. The plant kingdom represents a rich storehouse of organic compounds, many

of which have been used for medicinal purposes and could serve as primary source for the

development of novel agents having good efficacy in various pathological disorders in the

coming years. Any of the modern day drugs were actually derived from plants. Traditional

medicine involves the use of herbal medicine, animal parts and minerals and about 80% of

the world population is dependent (wholly or partially) on plant-based drugs.

Curcuma longa and Piper nigrum has been used for broad spectrum of diseases and their

isolated compound curcumin and piperine found to be anticarcinogenic and a potential

antioxidant. In the present research studies were carried out to observe the efficacy of crude

Curcuma longa and Piper nigrum extract against adriamycin induced genotoxicity in germ

cells of mice.

MATERIALS AND METHODS

Procurement and Identification of Plant Material

The plant material that is fresh rhizomes of Curcuma longa and Piper nigrum fruits were

procured from wholesale spice and herbs market, Hyderabad and were identified in

Department of Botany, Osmania University, Hyderabad. Fresh Curcuma longa rhizomes and

Piper nigrum fruits were cleaned and washed with deionised water, sliced and dried in the

sun for one week and again dried at 50°C in a hot air oven for 6 hours. Dried rhizomes were

cut in small pieces, powdered by electronic mill.


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Drugs and Chemicals

Adriamycin of Pfizer company was bought from Apollo Pharmacy, Hyderabad and Eosin

stain (Himedia). The chemicals and glassware used in the study are purchased from Rahul

Scientifics, Hyderabad,Telangana.

2.2. Preparation of the extract

Curcuma longa (Turmeric) rhizome and Piper nigrum fruits were collected from the local

Super market. Dry spices (100 gm) were crushed and sieved through mesh cloth to get the

fine powder. Powdered spices were soaked in 200ml of distilled water and were kept at room

temperature for 24 hours, then were filtered using Whatman no. 1 filter paper. The filtrate

was heated at 40-50°C using water bath, until thick paste is formed. The thick paste was

considered as 100% concentration of extract. These extracts were stored at 4°C in

refrigerator.[10]

2.3. Animals

Eight to ten weeks old male mice (Mus musculus) weighing about 25gm, procured from

National Institute of Nutrition, Hyderabad, were used in this study. The mice were housed in

polypropylene cages in a well ventilated room and were provided with standard pellet diet

(M/S Lipton India limited) and water ad libitum. They were maintained under controlled

conditions of temperature and light.

For Sperm Morphology Assay, in the first test three doses of Curcuma longa and Piper

nigrum fruits extract (CRE+PFE) i.e. 150+200, 250+300 and 350+400 mg/kg body weight

were administered for seven days and control group of animals were fed only with

physiological saline. In the second test animals were divided into groups and group I,group

II, group III, group IV and were given 16 mg/kg body wt adriamycin

(ADR),150+200(CRE+PFE)+16(ADR) mg/kg body wt, 250+300(CRE+PFE)+16(ADR)

mg/kg body wt, 350+400(CRE+PFE)+16g(ADR) mg/kg body wt respectively. Curcuma

longa rhizome and Piper nigrum fruits extract was dissolved in double distilled water and

administered as a single dose in 2 ml per mouse for 7days prior to adriamycin administration.

The drug was supplied by Apollo Pharmacy, Hyderabad. For each dose group three animals

were used and for each animal 500 sperms were screened. The animals were given

adriamycin intravenously in a single dose within 24 h interval. The control group of mice

received physiological saline simultaneously.


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2.4. Sperm Morphology Assay

All the exposed and control animals were sacrificed on last day of fifth week by cervical

dislocation after exposure to adriamycin. Spermatogonial stage which is exposed to drug

would reach to cauda epididymis after undergoing a series of changes during the process of

maturation to give rise to sperm. Animals were sacrificed and dissected out for both testis and

cauda epididymis, which were removed and placed in petridish containing 0.9% NaCl

(hypotonic physiological saline) solution. The cauda epididymis were teased thoroughly to

release the sperm and stained with 1% aqueos eosin for about 20-30 minutes. A drop of

sperm suspension was smeared on a clean slide. One thousand sperms per animal were scored

for each group for the presence of sperm shape abnormalities.[11]

2.5. Statistical analysis

For statistical evaluation of the experimental data Chi-Square test was performed. To

determine the frequency of various sperm head abnormalities about 500 sperms were scored

for each animal for the presence of amorphous, banana shaped, hammer headed, pin headed

sperms etc,. All the data was analysed for the significance of experimental versus control data

using the Chi-square test.

RESULTS AND DISCUSSION

Cytogenetic procedures are very helpful to evaluate the clastrogenic activity of chemicals

which are chief components of chemotherapy drugs that are responsible for genotoxicity. The

Sperm Morphology Assay functions as an important and sensitive indicator in assuming

reproductive genotoxicity. They can be used to estimate the spermatogenic impairment,

fertility and heritable genetic alterations. In the present investigation Sperm Morphology

Assay was conducted following the criteria of Wyrobek and Bruce (1975). As numerous

types of mutations can lead to abnormal sperm morphology, this test is treated as more

sensitive test in detecting germ cell mutagens than other germinal mutagenicity assays.[12]

Sperm morphology assay is also said to provide a quantitative technique for locating genetic

impairment in male germ line cells.

Analysis of Sperm Head abnormality assay in mice is being carried out in our laboratory

from last two decades and a lot of work has been carried out in our laboratory to test the

protective nature of different kinds of plant extracts against different kinds of drug induced

genotoxicity. Such as, Garlic extract against Cisplatin.[13]

Curcumin against Chromium.[14]

Curcumin against Cyclophosphamide.[15]

etc.


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A number of in vitro and in vivo experimentations revealed the therapeutic potential and

defensive effects of curcumin and piperine active ingredients of Curcuma longa and Piper

nigrum respectively. However in our investigation we intended to evaluate the modulating

effects of crude extract of Curcuma longa and Piper nigrum together against adriamycin

induced genotoxic damage. An effort has been made in the present experimentation to

evaluate whether such toxic effects induced by adriamycin are counteracted or counter

balanced by administration of Curcuma longa rhizome extract + Piper nigrum fruit extract.

In the current examination the higher occurrence of sperm abnormality induced by

adriamycin is a measure of genetic damage produced at the spermatogonial stage of the

mouse germ cells. In the current assessment the results on the incidence of sperm head

abnormalities in Curcuma longa rhizome extract + Piper nigrum fruit extract treated animals

are represented in Table 1. There is a slight rise in the percentage of abnormal sperms that is

2.00% in controls to 2.40, 2.93, 3.06 in 150CRE+200PFE, 250CRE+300PFE and

350CRE+400PFE mg/kg body weight Curcuma longa rhizome extract + Piper nigrum fruit

extract treated animals respectively. The variances in the incidence of sperm abnormalities

were found to be statistically insignificant when compared between control and Curcuma

longa rhizome extract + Piper nigrum fruit extract treated groups. Hence, the results clearly

indicate the antimutagenic nature of Curcuma longa rhizome extract + Piper nigrum fruit

extract. The results on the percentage of sperm abnormalities in Curcuma longa rhizome

extract + Piper nigrum fruit extract +Adriamycin treated mice are presented in Table 2. There

is a rise in the percentage of abnormal sperms that is 13.00% when adriamycin alone is

administered in a group compared to control group that is 2.00%. There is a gradual reduction

in the percentage of abnormal sperms that is 11.00, 9.06, 7.86 in16mg/kg ADR, 150+200 +16

mg/kg B.wt, 250 +300+16 mg/kg B.wt and 350 +400+16 mg/kg B wt. Curcuma longa

rhizome extract + Piper nigrum fruit extract +Adriamycin treated animals respectively when

compared to adriamycin alone treated group that is 13.00%. There is a significant reduction

in the occurrence of sperm head abnormalities in groups primed with Curcuma longa

rhizome extract (**P<0.01, *P<0.05).There is an increase in the percentage of inhibition in

the percentage of abnormal sperms with increase in the dose of Curcuma longa rhizome

extract + Piper nigrum fruit extract in Curcuma longa rhizome extract + Piper nigrum fruit

extract +Adriamycin treated animals. The percentage of inhibition by Curcuma longa

rhizome extract in 150+200 +16 mg/kg B.wt, 250 +300+16 mg/kg B.wt and 350 +400+16

mg/kg B wt. doses of Curcuma longa rhizome extract + Piper nigrum fruit extract


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+Adriamycin treated animals is 15.62 %, 33.75 % and 45.00% respectively (Table.2;

Graph.1). Various types of Sperm Abnormalities were shown in Fig (1).

Table 1: Frequency of sperm head abnormalities in mice administered with various

doses of Curcuma longa rhizome extract(CRE) and Piper nigrum Fruit extract (PFE).

Treatment dosage in mg/kg/bw Normal sperms Abnormal sperms

% %

Control 1470 98.00 30 2.00

150 CRE+200 PFE 1464 97.60 36 2.40%

250 CRE+300 PFE 1456 97.06 44 2.93%

350 CRE+ 400 PFE 1454 96.93 46 3.06%

The p>0.05 level, hence the difference is considered to be statistically insignificant.

Table 2: Frequency of sperm head abnormalities in Adriamycin treated mice primed

with Curcuma longa rhizome extract(CRE) and Piper nigrum Fruit extract (PFE).

Group Treatment & Dose

(mg/kg/bw)

Normal sperms Abnormal sperms % of

Inhibiti

on

% %

Group I Control 1470 98.00 30 2.00

Group II 16 mg/kg ADR 1310 87.00 190 13.00

Group III 150 CRE+200 PFE + 16 ADR 1335 89.00 165 11.00% 15.62

Group IV 250 CRE+300 PFE + 16 ADR 1364 90.93 136 9.06% 33.75

Group V 350 CRE+ 400 PFE + 16ADR 1382 92.13 118 7.86% 45.00

Table 3: χ2 values for the differences in the frequency of abnormal sperms in

adriamycin treated animals primed with CRE+PFE treated groups.

Treatment dose (mg/kg/bw) χ2 values

Control vs 16 mg/kg ADR 124.008**

16 ADR vs 150 CRE+200 PFE + 16 ADR 1.840

16 ADR vs 250 CRE+300 PFE + 16 ADR 9.667*

16 ADR vs 350 CRE+ 400 PFE + 16 ADR 18.239**

The p**<0.01 level, hence the difference is considered to be statistically extremely

significant.

p*<0.05 level, hence the difference is considered to be statistically significant.


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Various types of Sperm Abnormalities were shown in Fig(1).

Normal Sperm Amorphous Sickle shaped Banana Shaped

Hookless Head detached Hammer headed Pin headed

The major genetic effect of adriamycin and related compound is binding to DNA. It is

famous that adriamycin and other anthracyclines induce peroxide production in a range of

tissues. Cellular enzymes are able to convert adriamycin into free radical metabolites,

adriamycin cytotoxicity may be mediated by free radicals derived from this drug.[20]

The

present results are comparable with that of Meistrich et al[16]

who has studied sperm


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production and fertility in male mice treated with adriamycin (ADR) at 6 or 8 mg/kg body

weight. Testicular sperm production and epididymal sperm counts were markedly decreased

after adriamycin treatment. Gradual improvement of counts occurred but sperm counts have

not reached control levels even more than 1 year after treatment. Epididymal sperm

morphology indicated that adriamycin treatment induced morphological abnormalities all

through the test; the frequencies of sperm with detached tails and the frequencies of sperm

with morphologically abnormal heads continued to raise for about 2-3 fold above control.

Similarly Mestrich et al,[17]

declared that the mutagenic effect of Adriamycin on mouse

spermatogonial stem cells is tested by assessment of spermatocyte chromosome and of

dominant lethality transmitted through the spermatozoa. The effect of adriamycin on

mutation, cytotoxicity and sperm head abnormalities were compared with that of radiation.

The cytotoxic effect of 6GY of gamma-radiation on stem spermatogonia was equivalent to

about 4-5 mg/kg b.wt. adriamycin. Chromosomal translocations were observed in 6% of

spermatocyte of mice treated with adriamycin.

Curcuma longa is an obligatory food additive and an individual in his diet can consume 1-

5g/day of powdered form of Curcuma longa (Turmeric) which acts as a cleaning agent

renders to protect against many diseases.[18]

Several medical properties have been attributed to Curcuma longa Linn. Rhizome of Haridra

is known to possess therapeutic activities and has been used by medical practitioners as an

anti-diabetic,[19]

hypolipidemic,[20]

anti-inflammatory, anti-diarrhoeal.[18]

hepatoprotective.[19]

anti-asthmatic,[20]

and anti-cancerous drug. Haridra is widely used in cosmetology.[21]

The

fresh juice of Haridra is considered to be anthelmintic.[22]

Rhizome is used to treat cough and

cold. Hepatoprotective.[23]

Neuroprotective activity.[24]

Alzheimer’s disease symptoms

characterized by inflammation and oxidation were also eased by curcumin’s powerful

antioxidant and anti-inflammatory properties.[25]

Chemoprotective activity and anti cancer

activity.[26]

, anti allergic activity.[27]

, antidermatophytic activity.[21]

Curcumin has also been

shown as an immunostimulant and immunorestor in in vivo this mechanism may also

participate in cancer preventive activity.[28]

Curcumin has revealed strong antioxidant activity

and studies have shown curcumin to reduce oxidative stress. Hence it can conclude that

antioxidants such as curcumin protects the body from damage to free radicals.


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Black pepper is the world's most traded spice. It is one of the most common spices added to

European cuisine and its descendants. The spiciness of black pepper is due to the chemical

piperine. Black Pepper (or perhaps long pepper) was believed to cure illness such as

constipation, diarrhea, earache, gangrene, heart disease, hernia, hoarseness, indigestion,

insect bites, insomnia, joint pain, liver problems, lung disease, oral abscesses,sunburn, tooth

decay, and toothaches. As a medicine, pepper appears in the Buddhist Samannaphala Sutta,

chapter five, as one of the few medicines allowed to be carried by a monk.[29]

Piperine and

other components from black pepper may also be helpful in treating vitiligo.[30]

However,

extracts from black pepper have been found to have anti-carcinogenic effects, antioxidant,anti

inflammatory and antiulcer properties.[31,32]

respecially when compared to chili.[33]

Anti

inflammatory,[34]

Antidepressent nature,[35]

antioxidant properties,[36]

anti diabetic nature,[37]

Protective effects,[38] ]

Nephroprotective,[39]

It has been shown that piperine can dramatically

increase absorption of selenium, vitamin B,beta- carotene and curcumin as well as other

nutrients it means it works as a bioenhancer.[40,41,42]

Piperine and related compounds have been shown to reduce cell proliferation, angiogenesis

and metastasis in breast cancer cells. Piperine enhances the anti-cancer effects of curcumin,

the most biologically active component of turmeric.[43]

Piperine has been found to increase

the cytotoxicity of Adriamycin in drug resistant hormone receptor positive (ER+/PR+) breast

cancer cells. Now a new study has reported that piperine increases the cell-killing effects of

Taxol (paclitaxel) in HER2/neu overexpressing (HER2+) breast cancer cells.[43]

Curcumin the major component of Curcuma longa has been broadly studied for its

therapeutic properties. However, low oral bioavailability of curcumin has been proposed to

limit its agreement as a therapeutic agent. Studies have reported that curcumin gets reduced

through alcohol dehydrogenase, followed by conjugations like sulfation and glucuronidation

in liver and intestine.[44]

Curcumin when combined with piperine an active ingredient of Piper nigrum, piperine

proved to enhance the bioavailability of curcumin and to potentiate its protective effects

against chronic unpredictable stress induced cognitive impairment and associated oxidative

damage in mice.[45]

Chronic treatment with curcumin significantly enhanced behavioral and

biochemical changes induced by chronic unpredictable stress, recovered mitochondrial

enzyme complex activities, and inactivated increased acetylcholinesterase and serum


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corticosterone levels. In addition, co-administration of piperine with curcumin significantly

elevated the protective effect as compared to their effects alone.[46]

Further Banji et al.[47]

established that treated Wistar rats with piperine alone, curcumin or in

combination for a period of 49 days by the oral route with treatment being initiated a week

prior to D-galactose. A control group, D-galactose alone and naturally aged control were also

estimated. The results suggested a superior response to combination therapy compared to

monotherapy as proved by improved spatial memory, reduced oxidative burden, reduced

accumulation of lipofuscin, improvement in signaling, increase in hippocampal volume and

protection of hippocampal neurons. The powerful anti-oxidant nature of both, augmented

response of curcumin in the presence of piperine and enhanced serotoninergic signaling was

responsible for improved cognition and prevention in senescence.

Similar results were observed in another study where the piperine combined with curcumin

also proved to have a better anti-genotoxic effect compared to single treatment against

benzo(a)pyrene (BaP)-induced DNA damage in lungs and livers of mice.[48]

Curcumin and

piperine were administered separately as well as in combination orally in corn oil to swiss

albino mice for 7 days as pretreatments and subsequently, 2 h after, BaP was given orally in

corn oil. Pretreatments of curcumin and curcumin plus piperine before administration of

single dose of BaP significantly decreased percentage of DNA in the comet tail in both the

tissues. Moreover, the genoprotective potential of curcumin plus piperine was significantly

higher as compared to curcumin alone against BaP-induced DNA damage. The anti-cancer

property of curcumin is credited to its anti-oxidant properties.

CONCLUSION

Animals when treated with different doses of Curcuma longa rhizome extract + Piper nigrum

fruit extract revealed antimutagenic effect and the percentage of sperm head abnormalities

were nearly equal with that of control values. In the present investigation Adriamycin, a

chemotherapy drug presented significant rise in the frequency of abnormal sperm

morphology, but when animals primed with Curcuma longa rhizome extract + Piper nigrum

fruit extract, a significant inhibition of genotoxicity was observed in adriamycin treated

animals. Thus the overall results indicate the modulating effects of Curcuma longa rhizome

extract + Piper nigrum fruit extract against drug induced damage in swiss albino male mice.


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CRE alone, PFE alone and different doses of CRE, PFE together showed a significant

beneficial effect against ADR -induced genotoxicity. Combination groups reflect a

substantial amount of synergistic activity compared to CRE alone,PFE alone treated groups.

Among the combination groups, high -dose combination, that is, CRE (350mg/kg bw)

combined with PFE (400 mg/kg bw) shows the maximum modulating and antigenotoxic

effects. The efficacy of CRE and PFE could be attributed to the potential antioxidant activity

of curcumin and piperine respectively. The efficacy of CRE+PFE is contributed to both

curcumin and piperine along with bioenhancing property of Piper nigrum. In the combination

groups, bioavailability-enhancing effect of piperine further enhances the efficacy of

curcumin. Moreover, antioxidant property of piperine synergizes protective effects by

curcumin.

ACKNOWLEDGEMENTS

One of the authors J. Karuna Kumari is thankful for Award of fellowship under the scheme of

Maulana Azad National Fellowship for Minority Students to University Grants Commission,

New Delhi and Prof. K. Pratap Reddy, Head, Department of Zoology, Osmania University,

Hyderabad for providing Laboratory facilities.

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