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Malaysian Herbal Monograph
  • Written by Shahrul
  • Updated on December 18, 2024

Lada Hitam Fruit

Piper Nigrum L

Piperaceae

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Figure 1 : Piper nigrum (a) Tree; (b) leaves and fruits; (c) green fresh fruits, dried white peppercorns, dried black peppercorns (from left to right).

DEFINITION

Lada hitam fruit consists of dried fruit powder of Piper nigrum L. (Piperaceae) [ 1 ]

SYNONYM

None

VERNACULAR NAMES

Black pepper (English); lada hitam (Malay); hei hu jiao (Chinese); milagoo, milaagu, yavanappiriyam (Tamil) [ 1 , 2 ].

CHARACTER

ColourBlack [ 1 ]
OdourAromatic [ 1 ]
TasteHot bitter [ 1 ]

IDENTIFICATION

Plant Morphology

P. nigrum is a woody shrub and a climber, may reach 5 m long. Stem bark dark green with roots arising from the nodes, the stem branches by dichotomy and nodes are slightly swollen. Leaves opposite, ovate to lanceolate, cordate, upper surface of leaf dark green while underneath lighter green, 8-20 cm long, 5-15 cm wide. Inflorescence spike, 25 cm long,opposite leaf, the flower stalk 1-3.5 cm long, with a lanceolate sheath, 4-5 x 0.1 cm. Fruits green, unripe fruit is 3.5-6.0 mm diameter, almost globular. Black pepper is the dried fruit, very wrinkled surface and black in colour [ 1 ].

Microscopy

Powdered material consists of abundant large cells containing brown pigment, found in small groups; mostly are oblong; others are round to oval or irregular. Brachysclerids are very few, very large, almost as large as the brown pigmented cells. The powder has thick reticulated walls and pitted lumen, rectangular to oval. The scarce epidermal layer consists of polygonal to rectangular shaped cells with thick cell walls. Rosette calcium oxalate crystals are also observed [ 1 ].

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Figure 2 : Microscopic characters of P. nigrum dried fruitpowder. (a) Spiral vessel (magnification 400x); (b) annular vessel (magnification 400x); (c-d) rosette cluster calcium oxalate crystals of tetragonal system (magnification 400x); (e-f) thin-walled pentagonal parenchyma cells (magnification 400x); (g-h) lignified thick-walled parenchyma cells (magnification 400x);  (i-j) brachysclereids (magnification 400x); (k-l) starches (magnification 400x). [Scale bars: a-l = 20 µm]

Colour Tests 

Observed colour of solution after treatment with various reagents:

KOH (5%)Brown

Thin Layer Chromatography (TLC)

Figure 3 : TLC profiles of a piperine standard (S) and ethanol extract of P. nigrum dried fruit powder(L) observed under (a) UV 254 nm and (b) UV 366 nm.

Test Solutions Weigh about 1 g of P. nigrum dried fruit powder in a 250 mL round bottom flask and add 20 mL of ethanol. Sonicate the mixture for 10 min at 60°C. Filter the solution and evaporate to dryness on water bath. Reconstitute with 1 mL methanol and use as test solution.
Standard solution Dissolve piperine standard [CAS no.: 94-62-2] in methanol to produce 0.5 mg/mL solution.
Stationary Phase HPTLC Silica gel 60 F254, 10 x 10 cm
Mobile phase Hexane : ethyl acetate : dichloromethane; 5 : 3 : 2 (v/v/v)
Application
  1. Piperine standard solution (S); 10 µL, 8 mm as a band.
    Ethanol extract of P. nigrum driedfruit powder (L); 10 µL, 8 mm as a band.
Development distance 8 cm, automatic developing chamber 2 (ADC2)
Drying Air drying
Detection
  1. UV 254 nm.
  2. UV 366 nm

High Performance Liquid Chromatography (HPLC)

Test solution Weigh about 1 g of P. nigrum dried fruit powder with 20 mL ethanol in a flask. Sonicate the mixture for 10 min at 60°C. Filter the solution and evaporate to dryness on water bath. Reconstitute with 1 mL methanol. Further dilute 0.1 mL of the sample and top up with 0.9 mL methanol. Filter the mixture solution through a 0.45 µm syringe filter and inject the filtrate into the HPLC column.
Standard solution Dissolve piperine standard [CAS no.: 94-62-2] in methanol to produce 0.5 mg/mL solution.
Chromatographic system

Detector: UV 254 nm

Column: C18 (5 µm, 4.6 mm I.D x 250 mm)

Column oven temperature: 27ºC

Flow rate: 1.0 mL/min

Injection volume: 5 µL
Mobile Phase (Isocratic mode)

Isocratic elution using the mobile phase described below:

  1. A mixture of 75 volumes of methanol and 25 volumes of 0.1 % formic acid in water.
  2. Run time : 23 minutes
System suitability requirement

Perform at least five replicate injections of piperine standard solutions (0.5 mg/mL). The requirements of the system suitability parameters are as follow:

  1. Symmetry factor (As) is not more than 1.5.
  2. Percentage of relative standard deviation (RSD) of the retention time (tr) for piperine standard is not more than 2.0%.
Acceptance criteria

  1. Retention time (tr) of piperine in the test solution is similar to the tr of the standard solution.

The ultraviolet (UV) spectrum of piperine in the test solution is similar to the UV spectrum of the piperine in the standard solution (optional supportive data).
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Figure 4 : HPLC chromatogram of piperine standard solution (0.5 mg/mL) (a) full and (b) zoom at tr = 6.145 min

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Figure 5 : HPLC chromatogram of ethanol extract of P. nigrum driedfruit powder (a) full and (b) zoom showing peaks corresponding to piperine at tr = 6.156 min.

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Figure 6 : UV spectrum of piperine standard solution (0.5 mg/mL) and ethanol extract of P. nigrum dried fruit powder.

PURITY TESTS

Foreign Matter
Not more than 2%
Ash Contents
Total ash Not more than 7%
Acid-insoluble ash Not more than 1%
Loss on Drying
Not more than 17%
Extractive Values
Water-soluble extracts
Hot method Not less than 14%
Cold method Not less than 6%
Ethanol-soluble extracts
Hot method Not less than 6%
Cold method Not less than 4%

SAFETY TESTS

Heavy Metals
Arsenic Not more than 5.0 mg/kg
Mercury Not more than 0.5 mg/kg
Lead Not more than 10.0 mg/kg
Cadmium Not more than 0.3 mg/kg
Microbial Limits
Total bacterial count Not more than 105 cfu/g
Total yeast and mould count Not more than 104 cfu/g
Bile-tolerant gram negative Not more than 104 cfu/g
Specific Pathogens
Salmonella spp. Absent in 25 g
Escherichia coli Absent in 1 g
Staphylococcus aureus Absent in 1 g
Pseudomonas aeruginosa Absent in 1 g

CHEMICAL CONSTITUENTS

FRUIT

Methanol extract of P. nigrum fruits (black pepper) was found to contain alkamides (e.g. retrofractamide A, pipercide, piperchabamide D, pellitorin, dehydroretrofractamide C and dehydropipernonaline) [ 3 ].

Ethanol extracts were found to contain amide alkaloids (e.g. pipericine, piperine, [(2E,4E)-octadienoyl]-N-isobutylamide, [(2E)-hexadecanoyl]pyrrolidine, [(2E,4E)-octadecadienoyl]-N-isobutylamide, (2E,4E)-eicosadienoyl-N-isobutylamide, [(2E,4E)-octadecadienoyl]piperidine, pipercallosine,  tricholein, trichostachine, 1-piperettylpyrrolidine, ∆α,β-dihydrowisanidine, retrofractamide A, retrofractamide D, piperettine, pipwaqarine, piperamide-C5:1(2E), piperamide-C7:1(6E), piperamide-C7:2(2E,6E), piperamide-C9(8E), piperamide-C9:2(2E,8E), piperamide-C9:3(2E,4E,8E), 1-[(2E,4E)-2,4-decadienoyl]pyrrolidine, 1-[(2E,4E)-2,4-dodecadienoyl]pyrrolidine, piperylin, pipercide, guineensine and piperolein B and others (e.g. 30,40-methylenedioxycinnamaldehyde, β-caryophyllene, β-elemene and octadecanoic acid) [ 4 , 5 , 6 ].

Acetone extract was found to contain amides (e.g. (E,E)-N-(2-methylpropyl)- 2,4-decadienamide, (E,E,E)-13(1,3-benzodioxol-5-yl)-N(2-methylpropyl)-2,4,12-tridecatrienamide and  (E,E,E)-11-(1,3-benzodioxol-5-yl)-N-(2-methylpropyl)-2,4,10-undecatrienamide) [ 7 ].

Chloroform extracts were found to contain alkaloids (e.g. pipercyclobutanamides A and B) and sesquiterpene (e.g. β-caryophyllene) [ 8 , 9 ].

Petroleum ether (60-80°) extract was found to contain alkamide (e.g. isopiperolein B) [ 10 ].

Petroleum ether extracts were found to contain amides(e.g.2E,4E,8Z–N-isobutyleicosatrienamide, pellitorine, trachyone, pergumidiene, isopiperoleine B,  pipnoohine, pipyahyine, [(2E,4E)-octadienoyl]-N-isobutylamide, sarmentine, kalecide, [(2E,4E)-dodecadienoyl]pyrrolidine, pellitorine, hexadecanoylpyrrolidine, [(2E)-octadecanoyl]pyrrolidine, 1-[(2E,4E,12Z)-octadecatrienoyl]-N-isobutylamide, piptaline and 1-[7-(3,4-methylenedioxyphenyl)-(2E,4E)-heptadienoyl]-N-isobutylamide) and others (e.g. stigmastanol, β-sitosterol,  stigmasterol, stigmastanol 3-O–β–D-glucopyranoside, β-sitosterol 3-O–β–D-glucopyranoside, hexadecanoic ethyl ester, octadecanoic acid and 1-(3,4-methylenedioxyphenyl)-(1E)-tetradecene)
[ 11 , 12 ].

Hexane extract was found to containamides (e.g. piperine, piperolein B, pediculicide and (2E,4E)-N-isobutyl-2,4-decadienamide) [ 13 ].

Essential oil of P. nigrum fruits (black pepper) has been found to contain monoterpenoids (e.g. α-pinene, camphene, β-pinene, myrcene, 3-carene, δ-carene, β-carene, α-phellandrene, β-phellandrene, α-pinene oxide, limonene oxide, safrole, limonen-6-ol, limonene, γ-terpinene, ρ-cymene, terpinolene, α-thujene, citronellol, α-terpinene, δ-limonene, ρ-phellandrene, ocimene, 3-methylbutanal and methylpropanal, 1,8-cineol, linalool, α-terpineol, 1-terpinen-4-ol, 1-terpinen-5-ol, ρ-cymene-8-ol, ρ-cymen-8-ol-methyl ether,  trans-carveol, cis-carveol, trans-pinocarveol, dihydrocarveol, borneol, dihyrocarvone, nerol, carvacrol, (E)-β-ocimene, camphor, sabinene, cis– and trans-sabinene hydrate, m-mentha-3(8),6-diene (isosylveterpinolene) and carvone),   sesquiterpenoids (e.g. β-farnesene, trans-β-farnesene, (E)(E)-β-farnesene, α-humulene, nerolidol, (E)-nerolidol, δ-gurjunene, α-gurjunene, β-gurjunene, α-cububene, calarene, thujopsene, γ-muurolene, α-muurolol, β-cubebene, γ-cadinene, δ-cadinene,  cuparene, α-copaene, copaene, δ-guaiol, calamenene, cadinol, elemol, β-eudesmol and farnesol (Z,E)), bisabolane-type sesquiterpenoids (e.g. β-bisabolene, curcumene, ar-curcumene and α-curcumene), guaiane-type sesquiterpenoids (e.g. δ-guaiene and α-guaiene), elemane-type sesquiterpenoids (e.g. β-elemene, γ-elemene and δ-elemene), germacrane type (e.g. germacrene D, germacrene B and bicyclogermacrene) santalene-type sesquiterpenoid (e.g. α-santalene), bergamotene-type sesquiterpenoids (e.g. α-cis-bergamotene and α-trans-bergamotene), caryophyllane-type sesquiterpenoids (e.g. β-caryophyllene alcohol, isocaryophyllene, caryophyllene oxide, β-caryophyllene, epoxydihydrocaryophyllene, and trans-caryophyllene), sesquisabinane-type sesquiterpenoid (e.g. sesquisarbene), selinene-type sesquiterpenoids (e.g. α-selinene and β-selinene), cedrane-type sesquitepenoid (e.g. cedrene) and others (e.g.  cadina-1,4-diene, cis-piperitol, cyclosativene,  tricyclene, calamine, phenylacetic acid, cis-ρ.menthen-1-ol, cis-ρ.-2,8-methandien-1-ol, 2-undecanone, myrtenal, carvetonacetone,  myrtenol,  1(7),2-p-methadien-6-ol, 4,10,10-trimethyl-7-methylene bicycle [6.2.0]-decane-4-carboxaldehyde, caryophylla-3(12),7(15)-dien-4β-ol, caryophylla-2,7(15)-dien-4β-ol, caryophylla-2,7(15)-dien-4α-ol, cis-ρ-2- methen-1-ol, cis-ρ-2,8-menthadien-1-ol,  2-isopropyl-3-methoxypyrazine, 2,3-diethyl-5-methylpyrazine, 1-formylpiperidine, 1-acetylpiperidine, 2,3,5,6-tetramethylpyrazine, pyrazine, pyridine, cyclohexane, 1-methyl-4-(1-methylethylidene), 3-cyclohexen-1-ol, 4-methyl-1-(1-methylethyl), pivalate, (E)-3(10)-caren-4-ol, bicyclo[3.1.0]hexane, 4-methylene-1-(1-methylethyl), bufa-20,22-dienolide,14-hydroxy-3-oxo-(5á), 2-cyclohexen-1-ol, 1-methyl-4-(1-methylethyl)-, eudesma-4(14),11-diene, trans-9-octadecenoic acid, trimethylsilyl ester, 1,2-dihydropyridine, 1-(1-oxobutyl),1-chloroeicosane, β-pinone, 1,1,4-trimethylcyclohepta-2,4-dien-6-one,    3,8(9)-ρ-menthadien-1-ol, N-formyl piperidine, 1(7),2-p-methadien-4-ol, 5,10(15)-cadiene-4-ol, cryptone, methyl eugenol and myristicin) [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ].

SEEDS

Aqueous extract of P. nigrum seeds (black pepper) was found to contain choline and acetylcholine [ 34 ].

Ethanol extract was found to contain alkamides (e.g. guineensine, retrofracamide C, (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine, pipernonaline, piperrolein B, piperchabamide D, pellitorin and pipkirine), piperine, piperonal and pipercide) and others (e.g. stigmastanol, stigmasterol, stigmastanol glucoside, stigmasterol glucoside, cinnamylideneacetone, methylenedioxyphenylpropiophenone and 2-hydroxy-4,5-methylenedioxypropiophenone) [ 35 , 36 ].

Acetone extract was found to contain amide alkaloids (e.g. piperylin, piperine, N–trans-feruloyltyramine, retrofractamide A, piperamide, piperolein, piperettine and guineensine), lignin (e.g. hinokinin) and sesquiterpenes (e.g. torreyol, α-copaene, β-caryophyllene, β-bisabolene, δ-cadinene, spathulenol and caryophyllene oxide) [ 14 ].

Petroleum ether extract was found to contain amides (e.g. piptigrine, piperine, wisanine, pipsaeedine, pipbinine, (E,E)-N-(2-methylpropyl)dodeca-2,4-dienamide, (E,E)-N-(2-methylpropyl)hexadeca-2,4-dienamide, piptaline, piperanine, ∆,α,β-dihydrowisanidine,  ∆,α,β-dihydrowisanine, (E,E,E)-1-{[9-[3,4-(methylenedioxy)phenyl]nona-2,4,8-trienoyl}pyrrolidine, (E,E,E)-1-{11-[3,4-(methylenedioxy) phenyl]undeca-2,4,10-trienoyl}piperidine, 1-piperettylpyrrolidine and piperettine) and fatty acids (e.g. capric, lauric, myristic, palmitic, stearic, oleic, linoleic, malvalic, sterculic and vernolic) [ 37 , 38 , 39 ].

MEDICINAL USES

Uses described in folk medicine, not supported by experimental or clinical data

P. nigrum has been used in India for centuries as traditional remedies in Ayurvedic, Unani and Siddha medicines. It has been used for illnesses such as constipation, diarrhoea, earache, gangrene, heart disease, hernia, indigestion, insect bites, insomnia, joint pain, lung diseases, liver problems, tooth decay, toothache and treatment of eye problems by applying pepper salves or poultices directly onto the eyes [ 2 ].

P. nigrum has also been used as one of the ingredients of jamu tonic, indigestion mixture with ginger, electuary or paste mixed with honey and preparation for after childbirth. It has been used externally as a counter-irritant, as poultices for colic, rheumatism and headache, and by smearing on the body for after childbirth. P. nigrum oil could be used for cholera. High dose of P. nigrum with wild bamboo shoots may be used for abortion. Malay women have used P. nigrum pills with honey and ginger as an abortifacient [ 40 ].

In China, P. nigrum has also been used to dispel cold from stomach and to eliminate phlegm [ 41 ].

Biological and pharmacological activities supported by experimental data

Antibacterial activity
Amide alkaloids isolated from the petroleum ether extract of P. nigrum fruits exhibited antibacterial activity. 2E, 4E, 8Z–N-isobutyleicosatrienamide, trachyone and pergumidiene inhibited the Gram positive bacteria, i.e. Bacillus sphaericus (17, 30 and 29 μM, respectively), Bacillus subtilis (34, 30 and 58 μM, respectively) and Staphylococcus (34, 30 and 29 μM, respectively), as well as Gram negative bacteria, i.e. Klebsiella aerogenes and Chromobacterium violaceum, with MIC values of 70, 60, 58 μM with respect to the three compounds [ 45 ].

Antifungal activity
Acetone extract and essential oil from P. nigrum fruits (black pepper) were tested for their antifungal activity against various pathogenic fungi by inverted petriplate and food-poisoning techniques. In the food-poisoning technique, the essential oil (6 µL dose) possessed more than 80% activity in controlling the mycelial growth of Fusarium graminearum, Penicillium viridicatum and Curvularia lunata, and the extract (6 µL dose) inhibited 100% mycelial growth of Penicillium viridicatum and Aspergillus ochraceus. In inverted petriplate technique, only the essential oil (6 µL dose) was found to be 100% effective in controlling the mycelial growth of Fusarium graminearum and more than 70% effective against Aspergillus niger, Aspergillus oryzae and Penicillium madriti [ 46 ].

Antioxidant activity
Water and ethanol extracts of P. nigrum (75 mg/mL) significantly (p < 0.01) decreased DPPH free radical scavenging capacity at 55% and 48%, respectively, in comparison with positive controls; butylated hydroxyl anisole (79%), butylated hydroxytoluene (76%) and α-tocopherol (78%) [ 42 ].

Ethanol extract of P. nigrum fruit (250 μg/mL) exhibited a 74.61 ± 0.02% DPPH free radical scavenging capacity with (inhibitory concentration at 50% (IC50))value of 14.51 μg/mg
[ 43 ].

Two fractions (R2 and R3) of petroleum ether extract of P. nigrum fruits showed significant (p < 0.05) antioxidant activities via different mechanisms as compared to the respective positive controls including inhibition of lipid peroxidation in a linoleic acid emulsion (500 μg/mL; R2 = 58.79%, R3 = 60.48%, α-tocopherol = 76.47%), DPPH free radicals (250 μg/mL; R2 = 61.24%, R3 = 61.11%, butylated hydroxyl anisole = 82.59%), nitric oxide free radical generation (100 μg/mL; R2 = 40.23%, R3 = 55.68%, curcumin = 84.27%), superoxide anion radicals (100 μg/mL; R2 = 62.23%, R3 = 70.22%, butylated hydroxyl toluene = 81.54%) and hydroxyl radicals (1000 μg/mL; R2 = 61.04%, R3 = 63.56%, catechin = 70.95%) [ 44 ].

Anti-inflammatory
Piperine isolated from P. nigrum (5-40 mg/kg) administered orally to male albino Hindustan Antibiotics strain rats (100-125 g) showed a significant anti-inflammatory activity on carageenan-induced paw edema (45-240 min), except for the dose of 5 mg/kg BW at 45 min, with values in the range of 12 to 99.2% compared to the normal control (38.3-121.2%) and positive control, oxyphenyl butazone (OPB, 50 mg/kg: 17.2-48.7%) groups. In histamine and formaline-induced paw edema experiments, piperine gave 28.3% and 32.8% anti-inflammatory activity, respectively, compared to OPB group (32.8 and 38.1%, respectively). Piperine also exhibited anti-inflammatory activity in rats induced with cotton pellet granuloma with cotton pellets weight of 20.4 mg compared to normal control (36.21 mg) and OPB (22.60 mg) groups. The weight of granuloma of croton oil-induced inflammatory assay of rated treated with P. nigrum was 0.339 mg compared to normal control (0.846 mg) and OPB (0.321 mg) groups [ 47 ].

Intercellular cell adhesion molecules binding inhibitory activity
(2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine, pipernonaline, piperrolein B, pellitorin and dehydropipernonaline isolated from P. nigrum fruits inhibited direct binding between sICAM-1 (intercellular cell adhesion molecules) and LFA-1 (lymphocyte function associated antigen-1) of THP-1 cells (human monocytic leukaemia cell line) with IC50 values of 10.7, 8.8, 13.4, 13.5 and 6.0 μg/mL, respectively. Inhibitors of LFA-1/ICAM-1 mediated cell adhesion are potentially useful for the treatment of inflammatory diseases [ 48 ].

Immunomodultary activity
Polysaccharides, PN-Ib and PN-IIa, isolated from P. nigrum fruits showed significant (p < 0.05) anti-complementary activity with 50% inhibition of total complement hemolysis  (ITCH50) values of 96.5 ± 2.2% and 98.7 ± 1.9%, respectively, compared to the positive control, polysaccharide-K (60.2 ± 1.5%) [ 49 ].

Aqueous extract of P. nigrum fruits significantly enhance proliferation of T helper (Th)1 but suppress (Th)2 cytokine release by splenocytes dose-dependently[50 ].

Anti-cancer activity
Piperine isolated from P. nigrum was investigated for inhibition or reduction of the oxidative changes induced by chemical carcinogens in rat intestinal model. A segment of intestinal luminal of Charles foster male rats (150-200 g) was ligated and carcinogenesis-induced with 7,12-dimethyl benzanthracene (DMBA, 50 μg/mL), dimethyl amino-methyl azobenzene (DMAMAB, 20 mg/mL) and 3-methyl cholenthrene (3-MC, 3 mg/mL). Aqueous suspension of piperine in 1% carboxy methylcellulose equivalent to optimum concentration of 3.5 mM was exposed to the ligated segment. Piperine treatment with carcinogens significantly inhibited thiobarbituric reactive substances (TBARS) compared to DMBA-treated (p < 0.05), DMAMAB-treated (p < 0.01) and 3-MC-treated (p < 0.01) rat intestines. The carcinogens decreased levels of non-protein thiols (N-SH) in intestinal mucosa but exposure of piperine significantly (p < 0.01) decreased the levels. Piperine was also found to significantly reduce elevation of enzymes activities of γ-glutamyl transpeptidase (γ-GT) caused by DMAMAB and 3-MC (p < 0.001), as well as Na+-K+-ATPase induced by DMAMAB (p < 0.001), DMBA (p < 0.01) and 3-MC (p < 0.001). The study suggested a protective role of piperine against chemical carcinogen-induced oxidative stress [ 51 ].

Dried P. nigrum fruit (black pepper) powder (0.5% w/w mixed with the diet and 20% peanut oil) was administered orally daily for 30 weeks to male Wistar rats (100-120 g) with 1,2-dimethylhydrazine (DMH)-induced colon cancer. DMH-induced group treated with P. nigrum had smaller tumour size (0.5 cm) compared to DMH-induced control (2 cm). Presence of vascular granulation in the former animal group might indicate protective mechanism towards tumour development to deeper layers. Excretion of fecal bile acids and neutral sterols in 24-hour fecal samples was significantly (p < 0.05) increased in DMH-induced group treated with P. nigrum. P. nigrum given to DMH-induced group had lower (p < 0.05) cholesterol/phospholipid ratio (0.500-0.919) and increased 3-hydroxy-3-methylglutaryl (HMG-CoA) reductase activity (1.08-2.14) in the colon, intestine and liver compared to the DMH-induced control (0.818-1.567 and 0.85-1.68, respectively). The results showed that supplementation of P. nigrum prevented accumulation of lipids in tissues and optimized the excretion of fecal sterols and bile acids, suggesting the risk reduction of colon cancer in the presence of the procarcinogen DMH [ 52 ].

Antimutagenic activity
Aqueous extract of P. nigrum significantly (p < 0.05) reduced mutational events induced by promutagen agent ethyl carbamate using the wing somatic mutation and recombination test (SMART) in Drosophila melanogaster. P. nigrum reduced 38% (1% w/v) and 46% (2% w/v) of total number of spots [ 53 ].

Melanocyte proliferative activity
Aqueous extract of P. nigrum fruits (black pepper) (0.1 mg/mL) stimulated almost 300% growth of mouse melanocyte cell line, melan-a, in vitro in 8 days of experiment (p < 0.01) compared to piperine [ 54 ].

Chloroform extract of dried P. nigrum seeds (black pepper) (containing equivalent concentration of 1 μM piperine) stimulated proliferation of copiously pigmented non-tumorigenic mouse melanocyte cells (melan-a) in vitro greater than the pure piperine (1 µM piperine), suggesting that other phytochemical compounds were also responsible for the activity. Thus, piperine (p < 0.01), guineensine (p < 0.05), pipericide (p < 0.05), piperettine (p < 0.01) and piperlonguminine (p < 0.01) isolated from the chloroform extract, also stimulated proliferation of melanocytes at a concentration range of 0.1-10 µM, compared with the positive control 12-O-tetradecanoylphorbol-13-acetate (20 and 200 nM). The results suggested the potential use in vitiligo [ 55 ].

Gastrointestinal activity
Methanol (80%) extract of P. nigrum (1-10 mg/mL) possessed a spasmodic effect in guinea pig ileum at a concentration dependent manner of acetylcholine (Ach, 0.3 µM)-induced contractions with IC50 value of 0.7 mg/mL, compared to positive control loperamide and nifedipine with IC50 values of 5.9 µM and 0.3 µM, respectively. When tested against potassium (K+, 80 mM)-induced contractions, P. nigrum inhibited contraction with IC50 value of 0.6 mg/mL, compared to loperamide and nifedipine with respective IC50 values of 0.9 µM and 0.04 µM. P. nigrum extract (1000 mg/kg) produced 12.4% wet feces, compared to positive control, carbachol (47.1%). P. nigrum (500 and 1000 mg/kg) reduced castor oil-induced fluid accumulation with respective (Pi/Pm)x1,000 values of 143 and 90, compared to loperamide (78). P. nigrum extract (1000 mg/kg) exhibited 80% protective activity of castor oil-induced wet feces, compared to loperamide (10 mg/kg) as a positive control (p < 0.01) [ 56 ].

Utero-spasmolytic activity
Effect of aqueous extract of P. nigrum fruits on utero-spasmolytic activity was studied. Adult female Wistar rats (240-320 g) were injected subcutaneously with estradiol valerate (0.5 mg/kg) 24 hours prior to experiment. The rats were sacrificed and a piece (1-1.5 cm) of cervical portion of the uterus was dissected and mounted in an organ bath. The extract (0.125-2 mg/mL) dose-dependently (p < 0.01-0.001) reduced uterus contractions of KCl-induced (60 nM) greater than that of oxytocin-induced (10 mU/mL). The spasmolytic effect of extract on the KCl-induced contractions was not reduced by L-NAME (nitric oxide synthase inhibitor, 100 μM), phentolamine (α-adrenoceptor antagonist, 1 μM) and naloxone (opoid receptor antagonist, 1 μM), however the extract spasmolytic effect was reduced in the presence of propranolol (β-adrenoceptor antagonist, 1 μM) (p < 0.01-0.0001). The extract (0.0312-0.25 mg/mL) also reduced calcium chloride-induced uterus contraction dose-dependently. The study indicated that utero-spasmolytic effect of aqueous extract of P. nigrum was mediated via voltage dependent calcium channels and by inhibition of β-adrenoceptors [ 57 ].

Antidiabetic activity
Aqueous extract (0.5 mL/day) of P. nigrum seeds was administered orally to alloxan-induced diabetic on male albino Wistar rats once a day. After 4 weeks of experiment, blood glucose levels by treatment with the extract-treated group was 129 mg/100 mL compared to the insulin-treated (120 mg/100 mL), diabetic control (270 mg/100 mL) and normal control (102 mg/100 mL) groups. Total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) and triglycerides (TG) values of the extract-treated group were 172.0, 90.0, 58.7 and 130 mg/100 mL, respectively, comparable to the insulin-treated group (165.5, 95.2, 48.2 and 138.6 mg/100 mL, respectively). Similarly, the activity of liver anti-oxidative stress enzymes, such as catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) of the extract-treated group were 0.145 U/mg protein x 103, 15.68 U/mg protein and 0.131 U/mg protein, respectively, comparable to the insulin-treated group (0.138 U/mg protein x 103, 15.10 U/mg protein and 0.131 U/mg protein). The study suggested potential hypoglycemic effect of aqueous extract of P. nigrum seeds via antioxidant property [ 58 ].

Four alkamides, (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)2,4,8-nonatrienoyl]piperidine, pipernonaline, piperrolein B and dehydropipernonaline, isolated from chloroform extract of P. nigrum fruits inhibited acyl CoA:diacylglycerol acyltransferase (DGAT) in vitro with IC50 values of 29.8, 37.2, 20.1 and 21.2 µM, respectively. Inhibition of DGAT is associated with improved insulin sensitivity in vivo [ 59 ].

Hepatoprotective activity
P. nigrum powder (0.5, 1 and 2% w/w mixed with diet) was fed to random-bred Swiss albino mice of either sex (aged eight weeks old) for 10 and 20 days each. Hepatic glutathione S-transferase (GST) was significantly and dose-dependently increased in both sex groups (1 and 2% w/w for 10 days: 1.22-1.38 µM 1-chloro-2-4-dinitrobenzene (CDNB)-GSH conjugate formed/min/mg protein (p < 0.05) vs. normal control, 1.12-1.13 µM CDNB-GSH conjugate formed/min/mg protein; 0.5-2% w/w for 20 days: 1.35-1.74 µM CDNB-GSH conjugate formed/min/mg protein (p < 0.05) vs. normal control, 1.26-1.31 µM CDNB-GSH conjugate formed/min/mg protein); similarly with the estimated content of acid-soluble sulfhydryl (–SH) (1 and 2% w/w for 10 days: 5.05-5.57 µM/g tissue (p < 0.05) vs. normal control, 5.03-5.24 µM/g tissue; 1 and 2% w/w for 20 days: 6.79-7.20 µM/g tissue (p < 0.05) vs. normal control, 6.48-6.49 µM/g tissue). Cytochromes b5 and P-450 were also significantly (p < 0.05) and dose-dependently elevated for all doses and both time periods and sex groups with values in the range of 0.40-0.70 (cyt. b5) and 0.65-0.96 (cyt. P-450) nM/mg protein compared to the normal control (0.35-0.36 and 0.50-0.56 nM/mg protein for the respective cytochromes). Significant reduction (p < 0.05) of lipid peroxidation (expressed in terms of malondialdehyde) was only observed for 2% w/w P. nigrum treated groups for 20 days. The study suggested that P. nigrum could be a potential inducer of hepatic detoxication system [ 60 ].

Hydrocholagoguic activity
Suspension containing P. nigrum (black pepper) powder (250 and 500 mg/kg BW) in 1 mL aqueous dispersion of soluble starch was administered by force-fed gavage to male Wistar albino rats (330-390 g) for 4 weeks. Intragastric administration of P. nigrum (250 mg/kg) significantly (p < 0.05) increased bile solids content of 2.99% compared to normal control rats (2.77%). Feeding of P. nigrum for 4 weeks significantly increased bile flow (250 mg/kg: 0.87 mL/h, p < 0.001; 500 mg/kg: 0.74 mL/h, p < 0.05 compared to normal control: 0.54 mL/h), phospholipid (250 mg/kg: 1.78 μmol/h, p < 0.02 compared to normal control: 1.12 μmol/h) and total uronic acid (250 mg/kg: 2.80 μmol/h, p < 0.001; 500 mg/kg: 2.27 μmol/h, p < 0.05 compared to normal control: 1.68 μmol/h), but reduced bile solid content (250 mg/kg: 2.21%, p < 0.001; 500 mg/kg: 2.38%, p < 0.05 compared to normal control: 2.77%). Hydrocholagoguic effect was obtained due to increased bile flow with concomitant decrease in bile solids [ 61 ].

Antianderogenic activity
Ethanol (50%) extract of P. nigrum fruits (2 mg/mL) inhibited testosterone 5-alpha-reductase in vitro with a percentage inhibition of 63.0% compared to ethinylestradiol (1 mM, 63.3% inhibition), whereas piperine isolated from the fruits had IC50 value of 0.48 mM compared to ethinylestradiol (IC50 = 0.81 mM)[62].

Insecticidal activity
A study of insecticidal properties of P. nigrum fruit extracts and essential oils against tobacco army worm, Spodoptera litura has been done using topical application bioassay on uniform weighted second instar larvae in the laboratory. The result showed that, the hexane extract was the highest toxicity at 48 h after treatment and most effective in killing the larvae. Toxicity of extracts decreased in the order of hexane (LD50 1.8 mg/g) > acetone (LD50 18.8 mg/g) > chloroform (LD50 NA, the toxicity was very low) > essential oil (no mortality). Insect development and growth index observations showed that the hexane extract had antifeedant properties resulting in severe growth inhibition of Spodoptera litura
[ 63 ].

Petroleum ether extract of P. nigrum fruits (black pepper) was active against rice moth, Corcyra cephalonica (Stainton) 3rd instar larvae with median lethal concentration (LC50) values of 12.52 μL/mL. The result also showed that the extract had strong inhibition on egg hatchabilities and adult emergence of C. cephalonica at the lowest concentration [ 64 ].

Ethanol extract of P. nigrum (black pepper) (0.3 g) resulted in 100% mortality of millipede Orthoporus fuscipes after 4 days of exposure. However, only 70% mortality was achieved after 4 days of exposure to piperine (0.3 g) [ 65 ].

Ethanol extract of P. nigrum fruits (black pepper) had LC50 values of 0.405 ppm and 0.016 ppm against fourth and third instar larvae of A. aegypti, respectively. Hexane extract of black pepper was found to be more toxic against fourth larvae of A. aegypti with LC50 0.007 ppm [ 66 , 67 ].

Isobutylmide alkaloids isolated from P. nigrum fruits were found to have insecticidal activity against third instar larvae of Culex pipiens pallens (i.e. pipercide (LC50 0.004 ppm), retrofractamide A (0.028 ppm), guineensine (0.17 ppm) and pellitorine (0.86 ppm)), Aedes aegypti (i.e. retrofractamide A (0.039 ppm), pipercide (0.1 ppm), guineensine (0.89 ppm) and pellitorine (0.92 ppm)) and Aedes togoi (i.e. retrofractamide A (0.01 ppm), pipercide (0.26 ppm), pellitorine (0.71 ppm), and guineensine (0.75 ppm)). Piperine was the least toxic with LC50 values of 3.21, 5.1 and 4.6 ppm, respectively [ 68 ].

Piptigrine, pipsaeedine, pipbinine, pipnoohine, pipyahyine and pipwaqarine isolated from P. nigrum fruits exhibited toxicity against fourth instar larvae of A. aegypti with LC50 values of 15.0, 45.0, 40.0, 35.0, 30.0 and 30.0 ppm, respectively [ 5 , 69 , 70 , 71 ].

Insecticidal activity against female C. pipiens pallens was in the following order: pellitorine (LD50 values of 0.4 μg/female), guineensine (1.9), retrofractamide A (2.4) and pipercide (3.2) compared to chlorpyrifos (0.03 μg/female); whereas activity against A. aegypti was in the order of pellitorine (0.17), retrofractamide A (1.5), guineensine (1.7) and pipercide (2.0) compared to chlorpyrifos (0.0014 μg/female) [ 72 ].

Ethanol extract, piperolein-A and piperine isolated from P. nigrum fruits were found to be toxic against pyrethroid-resistant A. aegypti larvae with LC50 values of 0.98, 1.46 and 1.53 ppm, respectively [ 73 ].

Clinical studies

Information and data have not been established.

SAFETY INFORMATION

Preclinical studies (Toxicology studies)

Antispermatogenic and antifertility effects
P. nigrum fruit powder (25 and 100 mg/kg BW) was administered orally to male Parkes strain mice daily for 20 and 90 days. Administration of both doses of P. nigrum for 90 days significantly (p < 0.05) reduced weight of sex organs, such as testis (25 mg/kg: 213.04 mg/100 g BW; 100 mg/kg: 183.01 mg/100 g BW compared to vehicle control: 314.49 mg/100 g BW), epididymis (25 mg/kg: 82.97 mg/100 g BW; 100 mg/kg: 77.21 mg/100 g BW compared to vehicle control: 105.22 mg/100 g BW) and seminal vesicle (25 mg/kg: 179.05 mg/100 g BW; 100 mg/kg: 171.76 mg/100 g BW compared to vehicle control: 323.69 mg/100 g BW). Mice treated with 100 mg/kg BW dose for 90 days showed degenerative changes in all seminiferous tubules, including intraepithelial vacuolation, loosening of germinal epithelium, occurrence of giant cells, and mixing of spermatids of different stages of spermatogenesis; in severe cases, the tubules were lined by mainly a layer of Sertoli cells. Treatment for 90 days also caused detectable alteration in the duct, as well as adverse effects on sperm parameters, levels of sialic acid in epididymis (54.87 μmole/100 g tissue vs. control = 128.69 μmole/100 g tissue, p < 0.05) and fructose in seminal vesicle (55.07 μmole/100 g tissue vs. control = 222.21 μmole/100 g tissue, p < 0.05) [ 74 ].

Acute toxicity
Oral single dose acute toxicity study on female Sprague Dawley rats ( aged between 8 and 12 weeks old) using aqueous extract of P. nigrum fruits showed no toxic effect on the parameters observed, including behaviours, body weight, food and water intake. All rats were observed for 14 days prior to necropsy. No death was found throughout the study period. Necropsy revealed no significant abnormality. Approximate lethal dose (LD50) is more than 2,000 mg/kg body weight [ 75 ].

Others (Adverse reaction, contraindication, side effect, warning, precaution)

Information and data have not been established.

DOSAGE

In Ayurvedic practice, the recommended dosage is 250 mg-1g of P. nigrum powder [ 76 ].

STORAGE

Store below 30°C. Protect from light and moisture.

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