What is piperine
Piperine (1‐piperoyl piperidine) is a naturally occurring alkaloid of black pepper (Piper nigrum), long pepper (Piper longum) and other Piper species 1). Piperine constitutes approximately 5 to 9 percent of commercial black or white pepper. The sharp flavor of freshly ground pepper is attributed to the compound chavicine, a geometric isomer (having the same molecular formula but differing in structure) of piperine. The loss of pungency of ground pepper on storage is associated with slow transformation of chavicine into piperine. Piperine is ‘generally recognized as safe’ (GRAS) by the United States Food and Drug Administration (FDA) 2). Piperine is also known as a bioavailability enhancer or booster for promoting bioavailability of other drugs and has been shown to increase the bioavailability and pharmacological effects of some drugs in the body 3) and decrease the cytotoxicity of aflatoxin B1 and genotoxicity in vitro without leaving residues or its derivatives in the host 4) . Suresh and Srinivasan 5) showed that the amount of piperine in rat tissues (0.3%) reduced significantly after 48 hours, and was no longer detectable in the blood, liver, and intestine after 96 hours.
Piperine has been investigated extensively as a supportive nutrient for other compounds such as curcumin 6). In a randomized controlled trial that enrolled nonalcoholic fatty liver disease (NAFLD) patients, the supplementation of curcumin with piperine for 8 weeks improved nonalcoholic fatty liver disease (NAFLD), as shown by the ultrasound results of the patients 7). Choi et al. 8) also found that piperine alleviated high-fat diet-induced hepatic steatosis in mice in a dose-dependent manner. Although obesity is a risk factor for nonalcoholic fatty liver disease (NAFLD), the overlap between these two entities is incompletely understood 9). Okumura et al. 10) compared the actions of black pepper and piperine on adiposity suppression in the mice fed with a high-carbohydrate, high-fat diet for four weeks and found that black pepper suppressed the effect of body fat accumulation mainly through the action of piperine. Although several animal studies showed that piperine may have anti-obesity, lipid-lowering, and glucose-lowering properties 11), the mechanism of piperine on lipid metabolism and adipose tissue expansion in fat tissue remains still unclear. An animal study by Du et al 12) showed that piperine protects against obesity and improves lipid metabolism in mice fed with a high fat diet through the regulation of adipose tissue expansion related genes. Regarding the regulation of lipogenic and lipolytic target genes, piperine is more effective in visceral fat than in subcutaneous fat. However, further animal studies on this topic should investigate the potential effect modification by animal model, treatment dosage, intervention time, and administration routes.
Figure 1. Piperine chemical structure
Piperine, a naturally occurring alkaloid, has been demonstrated in test tube and animal studies as antifungal, anti-epileptic activities 13), anti-obesity 14), anti-gastric ulcer 15), anti-acute pancreatitis 16), and anti-arthritis 17), insecticidal 18), anti-oxidant 19), anti-inflammatory, antimicrobial 20), antiparasitic 21), antidepressant 22), antipyretic, analgesic, anti-inflammatory 23), anti-apoptotic 24), anti-mutagenic, anti-tumor and anti-proliferative agent. It has also been reported that piperine enhances the bioavailability of other phytochemicals 25) and drugs, for example, rifampcin 26) and resveratrol 27).
Recently, Zhang et al. 28) demonstrated the chemopreventive abilities of piperine against two osteosarcoma cell lines (HOS and U-2OS) metastasis and Greenshields et al. 29) demonstrated its protective properties against cancer cell migration in vitro through the inhibition of matrix metalloproteinase-2 and -9 expression.
Reen et al. 30) showed that piperine was able to significantly decrease the toxicity of aflatoxin B1 in rat hepatocytes in vitro and Selvendiran et al 31) demonstrated the protective effects of piperine against cytotoxic and genotoxic carcinogenesis induced by certain chemical carcinogens and aflatoxin B1.
Previous studies have shown that piperine possesses a number of pharmacological activities. Pharmaceutically, piperine has been reported to protect against hepatotoxicity 32), attenuate depressive disorders 33) and mitigate obesity and diabetes 34).
This naturally available non-toxic molecule has been used for the treatment of leukemia 35), as an insecticide against malaria Anopheles mosquitos 36) as well leshmianasis 37). Piperine also inhibits Akt phosphorylation 38) and suppresses angiogenesis as well as it exerts its anti-cancer effect by inhibiting CREB, NF-kB, c-Fos activities 39).
It is also noteworthy that the administration of piperine and its derivatives resulted in the activation of AMPKα signaling in mice 40). Piperine also decreased the phosphorylation of extracellular signal-regulated kinase (ERK) in vitro 41). These findings raised the possibility that piperine could protect against cardiac hypertrophy.
A double-blind, randomized placebo-controlled trial involving 55 patients with nonalcoholic fatty liver disease (NAFLD) showed that 500 mg curcumin supplementation (plus 5 mg piperine to increase intestinal absorption) for a period of 8 weeks can improve serum levels of inflammatory cytokines in subjects with nonalcoholic fatty liver disease (NAFLD) and this might be at least partly responsible for the anti-steatotic effects of curcuminoids 42). Curcumin supplementation improved the severity of nonalcoholic fatty liver disease (NAFLD) according to the ultrasound results. Moreover, serum concentrations of TNF-α, MCP-1 and EGF were improved by curcuminoids in nonalcoholic fatty liver disease (NAFLD) patients. The results also showed that supplementation with curcumin could decrease weight compared to the placebo group in patients with nonalcoholic fatty liver disease (NAFLD) 43).
Piperine side effects
Piperine is ‘generally recognized as safe’ (GRAS) by the United States Food and Drug Administration (FDA) 44). Recent studies have shown that the consumption of piperine is relatively safe, with low toxicity to cells of mammals and avian species 45).
There are no official recommendations for consumption of piperine and the maximum tolerable intake has not been identified.
References [ + ]
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|2.||↵||H. Jwa, Y. Choi, U.H. Park, S.J. Um, S.K. Yoon, T. Park. Piperine, an LXRalpha antagonist, protects against hepatic steatosis and improves insulin signaling in mice fed a high-fat diet. Biochemical Pharmacology, 84 (11) (2012), pp. 1501-1510, 10.1016/j.bcp.2012.09.009|
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|27.||↵||Johnson J. J. et al.. Enhancing the bioavailability of resveratrol by combining it with piperine. Mol. Nutr. Food Res. 55, 1169–1176 (2011).|
|28.||↵||Zhang J., Zhu X., Li H., Li B., Sun L., Xie T., Zhu T., Zhou H., Ye Z. Piperine inhibits proliferation of human osteosarcoma cells via G2/M phase arrest and metastasis by suppressing MMP-2/-9 expression. Int. Immunopharm. 2015;24:50–58. doi: 10.1016/j.intimp.2014.11.012|
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|40.||↵||Choi S., Choi Y., Choi Y., Kim S., Jang J., Park T. Piperine reverses high fat diet-induced hepatic steatosis and insulin resistance in mice. Food Chem. 2013;141:3627–3635.|
|41.||↵||Hwang Y.P., Yun H.J., Kim H.G., Han E.H., Choi J.H., Chung Y.C., Jeong H.G. Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCα/ERK1/2-dependent matrix metalloproteinase-9 expression. Toxicol. Lett. 2011;203:9–19.|
|44.||↵||GRAS Notice (GRN) No. 474 http://wayback.archive-it.org/7993/20171031042951/https://www.fda.gov/downloads/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/UCM362936.pdf|
|45.||↵||Cardoso V.S., Lima C.A.R., Lima M.E.F., Dorneles L.E.G., Direito G.M., Danelli M.G.M. Piperine as a phytogenic additive in broiler diets. Pesqui. Agropecu. Bras. 2012;47:489–496. doi: 10.1590/S0100-204X2012000400003|