Black pepper (Piper nigrum)

Pharmacology:

• Constituents: Black pepper has been found to contain piperine¹, alkamides⁹, piptigrine⁷, wisanine⁷, dipiperamide D¹⁰, and dipiperamide E¹⁰.
• Acetylcholinesterase inhibitory activity: In an in vitro study, an extract of Piper nigrum L. seeds showed 50-65% inhibitory activity on acetylcholinesterase.²
• Antibacterial effects: In an in vitro study using 12 different genera of bacterial populations isolated from the oral cavity of 200 individuals, an aqueous decoction of black pepper (Piper nigrum L.) exhibited 75% antibacterial activity as compared to aqueous decoction of bay leaf (53.4%) and aqueous decoction of aniseed (18.1%), at the concentration of 10mL/disc.⁴
• Anti-inflammatory effects: Based on animal study, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum demonstrated 31.3% inhibition against carrageenan-induced acute inflammation in Wistar Albino rats, while ibuprofen (50 mg/kg orally) exerted 68.1% inhibition.³ Aller-7 also exhibited a dose-dependent (150-350mg/kg) anti-inflammatory effect against Freund's adjuvant-induced arthritis in Wistar Albino rats; an approximately 63% inhibitory effect was observed at a dose of 350mg/kg.
• Antilarval activity: Piptigrine, isolated from the dried ground seeds of Piper nigrum Linn., exhibited toxicity of 15.0ppm against fourth instar larvae of Aedes aegypti Liston.⁷
• Antioxidant effects: Based on animal study, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum exhibited concentration-dependent scavenging activities toward biochemically generated hydroxyl radicals (IC₅₀ 741.73mcg/mL); superoxide anion (IC₅₀ 24.65mcg/mL by phenazine methosulfate-nicotinamide adenine dinucleotide [PMS-NADH] assay and IC₅₀ 4.27mcg/mL by riboflavin/nitroblue tetrazolium [NBT] light assay), nitric oxide (IC₅₀ 16.34mcg/mL); 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical (IC₅₀ 5.62mcg/mL); and 2,2-azinobis-ethyl-benzothiozoline-sulphonic acid diammonium salt (ABTS) radical (IC₅₀ 7.35mcg/mL).⁵ Aller-7 inhibited free radical-induced hemolysis in the concentration range of 20-80mcg/mL. Aller-7 also significantly inhibited nitric oxide release from lipopolysaccharide-stimulated murine macrophages.
• Cytochrome P (CYP) 450 effects: In in vitro studies, constituents isolated from Piper nigrum, including piperine and dipiperamides D and E, potently inhibited some CYP450 metabolic pathways, including CYP2D6⁹ and CYP3A4^8,10.
• Gastrointestinal effects: In a clinical study of intestinal peristalsis in 16 healthy volunteers, consumption of 1.5g of black pepper in capsules increased the orocecal transit time from 90 ± 51 minutes to 122 ± 88 minutes (p=0.09).¹¹ In an in vitro study, piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC₅₀ values of 15.5 and 74.1mcM, respectively.⁸ The bactericidal and anti-adhesive properties of black pepper have also been investigated against Helicobacter pylori, however, aqueous extracts did not show bactericidal effect on any of the isolates.⁶
• Neural effects: In an in vitro study using whole-cell patch-clamp electrophysiology, piperine, a pungent alkaloid found in black pepper, had similar agonist effects on the human vanilloid receptor TRPV1 as capsaicin.¹ However, piperine could induce greater receptor desensitization and exhibit a greater efficacy than capsaicin.

Pharmacodynamics/Kinetics:

• Pharmacokinetics: In an animal study, piperine from black pepper was shown to enhance the bioavailability of EGCG, a polyphenol constituent from green tea (Camellia sinensis).¹² Intragastric coadministration of 163.8mcM/kg EGCG and 70.2mcM/kg piperine to male CF-1 mice increased the plasma C_max and area under the curve (AUC) by 1.3-fold compared to mice treated with EGCG only. The authors report that piperine appeared to increase EGCG bioavailability by inhibiting glucuronidation and gastrointestinal transit. Piperine (100mmM/L) inhibited EGCG glucuronidation in mouse small intestine (by 40%), but not in hepatic microsomes. Piperine (20mcM/L) also inhibited production of EGCG-3"-glucuronide in human HT-29 colon adenocarcinoma cells. Small intestinal EGCG levels in CF-1 mice following treatment with EGCG alone had a C_max = 37.50 ± 22.50nM/g at 60 min that then decreased to 5.14 ± 1.65nM/g at 90 min; however, cotreatment with piperine resulted in a C_max = 31.60 ± 15.08nM/g at 90 min, and levels were maintained above 20nM/g until 180 min. This resulted in a significant increase in the small intestine EGCG AUC (4,621.80 ± 1,958.72 vs. 1,686.50 ± 757.07 (nM/g·min)). EGCG appearance in the colon and the feces of piperine-cotreated mice was slower than in mice treated with EGCG alone.
• Pharmacodynamics: Based on animal study, a polyherbal formulation (Aller-7/NR-A2) containing extracts from seven medicinal plants including Phyllanthus emblica, Terminalia chebula, Terminalia bellerica, Albizia lebbeck, Piper nigrum, Zingiber officinale, and Piper longum exhibited concentration-dependent scavenging activities toward biochemically generated hydroxyl radicals (IC₅₀ 741.73mcg/mL); superoxide anion (IC₅₀ 24.65mcg/mL by phenazine methosulfate-nicotinamide adenine dinucleotide [PMS-NADH] assay and IC₅₀ 4.27mcg/mL by riboflavin/nitroblue tetrazolium [NBT] light assay), nitric oxide (IC₅₀ 16.34mcg/mL); 1,1-diphenyl-2-picryl hydrazyl (DPPH) radical (IC₅₀ 5.62mcg/mL); and 2,2-azinobis-ethyl-benzothiozoline-sulphonic acid diammonium salt (ABTS) radical (IC₅₀ 7.35mcg/mL).⁵
• In an in vitro study, piperine inhibited digoxin and cyclosporine A transport in Caco-2 cells with IC₅₀ values of 15.5 and 74.1mcM, respectively.⁸

References

1. McNamara, F. N., Randall, A., and Gunthorpe, M. J. Effects of piperine, the pungent component of black pepper, at the human vanilloid receptor (TRPV1). Br J Pharmacol 2005;144(6):781-790. 15685214
2. Ingkaninan, K., Temkitthawon, P., Chuenchom, K., Yuyaem, T., and Thongnoi, W. Screening for acetylcholinesterase inhibitory activity in plants used in Thai traditional rejuvenating and neurotonic remedies. J Ethnopharmacol 2003;89(2-3):261-264. 14611889
3. Pratibha, N., Saxena, V. S., Amit, A., D'Souza, P., Bagchi, M., and Bagchi, D. Anti-inflammatory activities of Aller-7, a novel polyherbal formulation for allergic rhinitis. Int J Tissue React<.em> 2004;26(1-2):43-51. 15573692
4. Chaudhry, N. M. and Tariq, P. Bactericidal activity of black pepper, bay leaf, aniseed and coriander against oral isolates. Pak J Pharm Sci 2006;19(3):214-218. 16935829
5. D'Souza, P., Amit, A., Saxena, V. S., Bagchi, D., Bagchi, M., and Stohs, S. J. Antioxidant properties of Aller-7, a novel polyherbal formulation for allergic rhinitis. Drugs Exp Clin Res 2004;30(3):99-109. 15366786
6. O'Mahony, R., Al Khtheeri, H., Weerasekera, D., Fernando, N., Vaira, D., Holton, J., and Basset, C. Bactericidal and anti-adhesive properties of culinary and medicinal plants against Helicobacter pylori. World J Gastroenterol 12-21-2005;11(47):7499-7507. 16437723
7. Siddiqui, B. S., Gulzar, T., Begum, S., and Afshan, F. Piptigrine, a new insecticidal amide from Piper nigrum Linn. Nat Prod Res 2004;18(5):473-477. 15248617
8. Bhardwaj, R. K., Glaeser, H., Becquemont, L., Klotz, U., Gupta, S. K., and Fromm, M. F. Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002;302(2):645-650. 12130727
9. Subehan, Usia, T., Kadota, S., and Tezuka, Y. Mechanism-based inhibition of human liver microsomal cytochrome P450 2D6 (CYP2D6) by alkamides of Piper nigrum. Planta Med 2006;72(6):527-532. 16808005
10. Tsukamoto, S., Tomise, K., Miyakawa, K., Cha, B. C., Abe, T., Hamada, T., Hirota, H., and Ohta, T. CYP3A4 inhibitory activity of new bisalkaloids, dipiperamides D and E, and cognates from white pepper. Bioorg Med Chem 2002;10(9):2981-2985. 12110320
11. Vazquez-Olivencia, W., Shah, P., and Pitchumoni, C. S. The effect of red and black pepper on orocecal transit time. J Am Coll Nutr 1992;11(2):228-231. 1578101
12. Lambert, J. D., Hong, J., Kim, D. H., Mishin, V. M., and Yang, C. S. Piperine enhances the bioavailability of the tea polyphenol (-)-epigallocatechin-3-gallate in mice. J Nutr 2004;134(8):1948-1952. 15284381

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