Absence of adverse effects following administration of piperine in the diet of Sprague-Dawley rats for 90 days

Bastaki, Maria; M, Aubanel; Bauter, Mark R.; Cachet, Thierry; Demyttenaere, Jan; Diop, Maodo Malick; Harman, Christie L.; Hayashi, Shim-mo; Krammer, Gerhard; Li, Xiaodong; Llewellyn, Craig H.; Mendes, Odete; Renskers, Kevin J.; Schnabel, Jürgen; Smith, Benjamin; Taylor, Sean V.

doi:10.1016/j.fct.2018.06.055

Cited by 18 publications

(15 citation statements)

References 35 publications

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“…Hu et al (2015) further revealed that the anti-colitis effect of piperine is independent of PXR activation, evidencing by the anti-colitis effect of piperine can be reversed by tail vein injection of PXR small interfering RNA (siRNA). The relative safe characteristic of piperine have been clearly stated in the toxicologic experiments (Piyachaturawat et al, 1983; Chinta et al, 2017; Bastaki et al, 2018). In adult male mice the LD50 value of piperine on intravenous, intraperitoneal, intramuscular, intragastric and subcutaneous orally administration were 15.1, 43, 400, 330, and 200 mg/kg, respectively; In parallel, the LD50 value of piperine on intraperitoneal route in adult female mice and weanling male mice were 60 and 132 mg/kg, respectively.…”

Section: Plant-based Alkaloids Against Ibdmentioning

confidence: 98%

“…As well, in adult femate rats, the LD50 value of piperine on intraperitoneal administration was 33.5 mg/kg whereas was increased to 514 mg/kg on intragastric route (Piyachaturawat et al, 1983). Bastaki et al (2018) performed 90-day Good Laboratory Practice (GLP) compliant dietary study of piperine in rats and found that no adverse effects were observated when the rats giving piperine up to 50 mg/kg.…”

Section: Plant-based Alkaloids Against Ibdmentioning

confidence: 99%

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Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

Jiao

Zheng

et al. 2019

Front. Pharmacol.

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Inflammatory bowel disease (IBD) represents a group of intestinal disorders with self-destructive and chronic inflammation in the digestive tract, requiring long-term medications. However, as many side effects and drug resistance are frequently encountered, safer and more effective agents for IBD treatment are urgently needed. Over the past few decades, a variety of natural alkaloids made of plants or medicinal herbs have attracted considerable interest because of the excellent antioxidant and anti-inflammatory properties; additionally, these alkaloids have been reported to reduce the colonic inflammation and damage in a range of colitic models. In this review paper, we summarize the recent findings regarding the anti-colitis activity of plant-derived alkaloids and emphasize their therapeutic potential for the treatment of IBD; obvious improvement of the colonic oxidative and pro-inflammatory status, significant preservation of the epithelial barrier function and positive modulation of the gut microbiota are the underlying mechanisms for the plant-derived alkaloids to treat IBD. Further clinical trials and preclinical studies to unravel the molecular mechanism are essential to promote the clinical translation of plant-derived alkaloids for IBD.

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Section: Plant-based Alkaloids Against Ibdmentioning

confidence: 98%

Section: Plant-based Alkaloids Against Ibdmentioning

confidence: 99%

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

Jiao

Zheng

et al. 2019

Front. Pharmacol.

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“…The European Food Safety Authority (EFSA) has evaluated the use of piperine as a flavouring substance. In its evaluations, EFSA (2008;2011;2015) disagreed with a No Observed Effect Level (NOEL) of 20 mg piperine/kg bw/day that had previously been identified by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) (2006), due to the shortcomings of the underlying animal study (lack of histopathology, study duration) and in 2015 identified a No Observed Adverse Effect Level (NOAEL) of 5 mg piperine/kg bw/day, based on a newly available 90-day rat feeding study performed according to OECD guideline 408 (endpoint: dose-dependent increase in cholesterol level in male animals) [29,32,[48][49][50] (see (2) in Section 4.2.2). In its final conclusion, EFSA (2015) agreed with the JECFA (2006) conclusion "no safety concern at estimated levels of intake as flavouring substance" based on the MSDI approach (estimated European per capita intake by the MSDI approach: 6.2 µg piperine/day) [32,50].…”

Section: Information Based On Evaluations By Scientific Bodies and National Authoritiesmentioning

confidence: 99%

“…The subchronic toxicity study (90-day study) in rats that was finalised in 2013 and used by EFSA (2015) [32] for the assessment of piperine as a flavouring agent has been published meanwhile (Bastaki et al (2018) [29]). In this study, 0, 5, 15 or 50 mg piperine/kg bw/day were administered via feed for 90 days.…”

Section: Animal Studiesmentioning

confidence: 99%

Safety Aspects of the Use of Isolated Piperine Ingested as a Bolus

Ziegenhagen

Heimberg

Lampen

et al. 2021

Foods

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Piperine is a natural ingredient of Piper nigrum (black pepper) and some other Piper species. Compared to the use of pepper for food seasoning, piperine is used in food supplements in an isolated, concentrated form and ingested as a bolus. The present review focuses on the assessment of the possible critical health effects regarding the use of isolated piperine as a single ingredient in food supplements. In human and animal studies with single or short-term bolus application of isolated piperine, interactions with several drugs, in most cases resulting in increased drug bioavailability, were observed. Depending on the drug and extent of the interaction, such interactions may carry the risk of unintended deleteriously increased or adverse drug effects. Animal studies with higher daily piperine bolus doses than in human interaction studies provide indications of disturbance of spermatogenesis and of maternal reproductive and embryotoxic effects. Although the available human studies rarely reported effects that were regarded as being adverse, their suitability for detailed risk assessment is limited due to an insufficient focus on safety parameters apart from drug interactions, as well as due to the lack of investigation of the potentially adverse effects observed in animal studies and/or combined administration of piperine with other substances. Taken together, it appears advisable to consider the potential health risks related to intake of isolated piperine in bolus form, e.g., when using certain food supplements.

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“…Using modern drug safety evaluation system, Bastaki M et al organized a 90-day GLP compliant toxicity study in sprague-dawley rats with multiple doses of piperine (5-50 mg/kg bw/day) to evaluate the safety of daily uptake of piperine in foods. Notably, no adverse effects were observed following piperine ingestion even at the highest dosage (50 mg/kg bw/day) (Bastaki et al, 2018). Herein, we present data that piperine has the ability to interact with DHODH and reduce T cell proliferation via a DHODH dependent manner.…”

Section: Discussionmentioning

confidence: 73%

Natural Product Piperine Alleviates Experimental Allergic Encephalomyelitis in Mice by Targeting Dihydroorotate Dehydrogenase

Liu

wang

et al.

Authorea

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BACKGROUND AND PURPOSE Human dihydroorotate dehydrogenase (DHODH) represents a promising therapeutic target for chronic inflammatory and autoimmune diseases. The aim of this study was to discover novel DHODH inhibitor and evaluate the potential of DHODH inhibition in treating multiple sclerosis (MS), a popular chronic inflammatory disease of the central nervous system. EXPERIMENTAL APPROACH Biochemical and Biophysical methods, including enzymatic kinetic analysis, thermofluor assay, isothermal titration calorimetry and X-ray crystallography were used to assess DHODH inhibition. The immunomodulatory activity was assessed by using concanavalin a-triggered T-cell assay and mixed lymphocyte reaction assay. MOG-induced experimental allergic encephalomyelitis (EAE) was used to assess the in vivo therapeutic effects. Myelin destruction and blood-brain barrier (BBB) was evaluated via in vivo imaging KEY RESULTS Piperine was identified as a natural inhibitor of human DHODH with an IC50 value of 0.88 ± 0.04 μM. In addition, we resolved the co-complex crystal structure of DHODH and piperine at 1.98Å resolution and found that Tyr356 residue of DHODH is critical for piperine binding. Moreover, piperine can markedly suppress T cell overactivation via a DHODH dependent-manner. Finally, we found that piperine exhibits strong preventive and therapeutic effect in the MOG-induced EAE by restricting inflammatory cells infiltration into the CNS and by preventing myelin destruction and blood-brain barrier (BBB) disruption. CONCLUSION AND IMPLICATIONS Taken together, these findings highlight DHODH as a therapeutic target for autoimmune disease of the nervous system, and demonstrate a novel pharmacological role for piperine in the treatment of MS. EXPERIMENTAL APPROACH Biochemical and Biophysical methods, including enzymatic kinetic analysis, thermofluor assay, isothermal titration calorimetry and X-ray crystallography were used to assess DHODH inhibition. The immunomodulatory activity was assessed by using concanavalin a-triggered T-cell assay and mixed lymphocyte reaction

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Absence of adverse effects following administration of piperine in the diet of Sprague-Dawley rats for 90 days

Cited by 18 publications

References 35 publications

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

Plant-Derived Alkaloids: The Promising Disease-Modifying Agents for Inflammatory Bowel Disease

Safety Aspects of the Use of Isolated Piperine Ingested as a Bolus

Natural Product Piperine Alleviates Experimental Allergic Encephalomyelitis in Mice by Targeting Dihydroorotate Dehydrogenase

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