title: Piperine inhibits the activities of platelet cytosolic phospholipase A2 and thromboxane A2 synthase without affecting cyclooxygenase-1 activity: different mechanisms of action are involved in the inhibition of platelet aggregation and macrophage inflammatory response.
abstract: OBJECTIVE
  Piperine, a major alkaloid of black pepper (Piper nigrum) and long pepper (Piper longum), was shown to have anti-inflammatory activity through the suppression of cyclooxygenase (COX)-2 gene expression and enzyme activity. It is also reported to exhibit anti-platelet activity, but the mechanism underlying this action remains unknown. In this study, we investigated a putative anti-platelet aggregation mechanism involving arachidonic acid (AA) metabolism and how this compares with the mechanism by which it inhibits macrophage inflammatory responses;
  
  
  METHODS
  Rabbit platelets and murine macrophage RAW264.7 cells were treated with piperine, and the effect of piperine on the activity of AA-metabolizing enzymes, including cytosolic phospholipase A2 (cPLA2), COX-1, COX-2, and thromboxane A2 (TXA2) synthase, as well as its effect on AA liberation from the plasma membrane components, were assessed using isotopic labeling methods and enzyme immunoassay kit;
  
  
  RESULTS
  Piperine significantly suppressed AA liberation by attenuating cPLA2 activity in collagen-stimulated platelets. It also significantly inhibited the activity of TXA2 synthase, but not of COX-1, in platelets. These results suggest that piperine inhibits platelet aggregation by attenuating cPLA2 and TXA2 synthase activities, rather than through the inhibition of COX-1 activity. On the other hand, piperine significantly inhibited lipopolysaccharide-induced generation of prostaglandin (PG)E2 and PGD2 in RAW264.7 cells by suppressing the activity of COX-2, without effect on cPLA2;
  
  
  CONCLUSIONS
  Our findings indicate that piperine inhibits platelet aggregation and macrophage inflammatory response by different mechanisms.
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu 702-701, Korea. sondj1@hotmail.com.
authors.forename: Dong Ju
authors.initials: DJ
authors.lastname: Son
authors.affiliation: Department of Pathological Biochemistry, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. akiba@mb.kyoto-phu.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akiba
authors.affiliation: College of Pharmacy and Center for Innovative Cancer Therapeutics, Chungbuk National University, Cheongju 361-763, Korea. jinthong@chungbuk.ac.kr.
authors.forename: Jin Tae
authors.initials: JT
authors.lastname: Hong
authors.affiliation: College of Pharmacy and Center for Innovative Cancer Therapeutics, Chungbuk National University, Cheongju 361-763, Korea. ypyun@chungbuk.ac.kr.
authors.forename: Yeo Pyo
authors.initials: YP
authors.lastname: Yun
authors.affiliation: Department of Biomedical Laboratory Science, College of Natural Science, Daejeon 300-716, Korea. syhwang@dju.ac.kr.
authors.forename: Seock Yeon
authors.initials: SY
authors.lastname: Hwang
authors.affiliation: Department of Food Science and Nutrition, College of Natural Sciences, Soonchunhayng University, Asan 336-745, Korea.
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Park
authors.affiliation: School of Applied Biosciences, Kyungpook National University, Daegu 702-701, Korea. selpest@knu.ac.kr.
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Lee
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D052117:Benzodioxoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D064801:Phospholipase A2 Inhibitors / Q000494:pharmacology; D054467:Phospholipases A2 / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D011817:Rabbits; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D052117:Benzodioxoles; D064801:Phospholipase A2 Inhibitors; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D053284:Polyunsaturated Alkamides; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D054467:Phospholipases A2; D013930:Thromboxane-A Synthase; C008922:piperine