The 2′,4′,6′-Trihydroxyacetophenone Isolated from Myrcia multiflora Has Antiobesity and Mixed Hypolipidemic Effects with the Reduction of Lipid Intestinal Absorption

Abstract

This study evaluated the hypolipidemic and antiobesity effects of phloroacetophenone (2′,4′,6′-trihydroxyacetophenone, THA) isolated from Myrcia multiflora and their relationship with triglyceride (TG) intestinal absorption and pancreatic lipase activity inhibition. The hypolipidemic effect of THA was evaluated by acute (Triton WR-1339 treatment) and chronic assay (high-fat diet treatment), the antiobesity effect was evaluated by chronic assay (high-fat diet treatment), while the inhibition of enzymatic activity of pancreatic lipase was measured in the intestinal tissue of mice treated with high olive oil concentration. In the acute assay, THA caused greater total cholesterol (37 %) and triglyceride (46 %) serum level reduction than lovastatin (32 and 1 %), a HMG‐CoA reductase inhibitor or orlistat (26 and 34 %), a gastrointestinal lipase inhibitor. In addition, in the chronic assay with a high-fat diet, THA reduced cholesterol and triglyceride levels (32 and 61 %, respectively) while lovastatin showed a decrease of 35 and 49 %, respectively. THA also caused a reduction in weight gain very similar to orlistat (40 and 38 %, respectively) when the animals were submitted to a high-fat diet. Moreover, THA showed a stronger and continuous pancreatic lipase inhibitory activity when compared with orlistat, causing inhibition of this enzyme during 6 hours associated to a significant reduction of triglyceride serum levels. The in vivo antiobesity and hypolipidemic effects of THA may be partly mediated by delaying the intestinal absorption of dietary fat by inhibiting pancreatic lipase activity.

Key words

antiobesity effect - mixed hypolipidemic activity - Myrcia multiflora - Myrtaceae - pancreatic lipase inhibitor - 2′,4′,6′‐trihydroxyacetophenone

References

• 1 Friedman J M. Obesity: Causes and control of excess body fat.  Nature. 2009;  459 340-342
• 2 World Health Organization (WHO) .Fact sheet: obesity and overweight. http://www.who.int/mediacentre/factsheets/fs311/en/print.html Accessed May 9, 2009
• 3 Weaver J U. Classical endocrine diseases causing obesity.  Front Horm Res. 2008;  36 212-228
• 4 Ofir D, Laveneziana P, Webb K A, O'Donnell D E. Ventilatory and perceptual responses to cycle exercise in obese women.  J Appl Physiol. 2007;  102 2217-2226
• 5 Sørensen T I, Virtue S, Vidal-Puig A. Obesity as a clinical and public health problem: Is there a need for a new definition based on lipotoxicity effects?.  Biochim Biophys Acta. 2010;  1801 400-404
• 6 Eckel R H. Clinical practice. Nonsurgical management of obesity in adults.  N Engl J Med. 2008;  358 1941-1950
• 7 Flegal K M, Graubard B I, Williamson D F, Gail M H. Cause-specific excess deaths associated with underweight, overweight, and obesity.  JAMA. 2007;  298 2028-2037
• 8 Marinou K, Tousoulis D, Antonopoulos A S, Stefanadi E, Stefanadis C. Obesity and cardiovascular disease: from pathophysiology to risk stratification.  Int J Cardiol. 2010;  138 3-8
• 9 Friedman J M. A war on obesity, not the obese.  Science. 2003;  299 856-858
• 10 Lenz M, Richter T, Mühlhauser I. The morbidity and mortality associated with overweight and obesity in adulthood: a systematic review.  Dtsch Arztebl Int. 2009;  106 641-648
• 11 Woo M N, Bok S H, Lee M K, Kim H J, Jeon S M, Do G M, Shin S K, Ha T Y, Choi M S. Anti-obesity and hypolipidemic effects of a proprietary herb and fiber combination (S & S PWH) in rats fed high-fat diets.  J Med Food. 2008;  11 169-178
• 12 Bamba V, Rader D J. Obesity and atherogenic dyslipidemia.  J Gastrol. 2007;  132 2181-2190
• 13 Kuo D H, Yeh C H, Shieh P C, Cheng K C, Chen F A, Cheng J T. Effect of shanzha, a Chinese herbal product, on obesity and dyslipidemia in hamsters receiving high-fat diet.  J Ethnopharmacol. 2009;  124 544-550
• 14 Zalesin K C, Franklin B A, Miller W M, Peterson E D, McCullough P A. Impact of obesity on cardiovascular disease.  Endocrinol Metab Clin N Am. 2008;  37 663-684
• 15 Lee K R, Hong S W, Kwak J H, Pyo S, Jee O P. Phenolic constituents from the aerial parts of Artemisia stolonifera.  Arch Pharm Res. 1996;  19 231-234
• 16 Chosson E, Chaboud A, Chulia A J, Raynaud J. A phloroacetophenone glucoside from Rhododendron ferrugineum.  Phytochemistry. 1998;  47 87-88
• 17 Dai Y, He X J, Zhou G X, Kurihara H, Ye W C, Yao X S. Acylphloroglucinol glycosides from the fruits of Pyracantha fortuneana.  J Asian Nat Prod Res. 2008;  10 111-117
• 18 Yoshikawa M, Shimada H, Nishida N, Li Y, Toguchida I, Yamahara J, Matsuda H. Antidiabetic principles of natural medicines. II. Aldose reductase and alpha-glucosidase inhibitors from Brazilian natural medicine, the leaves of Myrcia multiflora DC. (Myrtaceae): structures of myrciacitrins I and II and myrciaphenones A and B.  Chem Pharm Bull. 1998;  46 113-119
• 19 Matsuda H, Nishida N, Yoshikawa M. Antidiabetic principles of natural medicines. V. Aldose reductase inhibitors from Myrcia multiflora DC. (2): Structures of myrciacitrins III, IV, and V.  Chem Pharm Bull. 2002;  50 429-431
• 20 Suksamrarn A, Eiamong S, Piyachaturawat P, Byrne L T. A phloracetophenone glucoside with choleretic activity from Curcuma comosa.  Phytochemistry. 1997;  45 103-105
• 21 Brandão M G L, Nery C G C, Mamão M A S, Krettli A U. Two methoxylated flavone glycosides from Bidens pilosa.  Phytochemistry. 1998;  48 397-399
• 22 Zhao L M, Jin H S, Sun L P, Piao H R, Quan Z S. Synthesis and evaluation of antiplatelet activity of trihydroxychalcone derivatives.  Bioorg Med Chem Lett. 2005;  15 5027-5029
• 23 Vásquez-Freire M J, Lamela M, Calleja J M. Hypolipidaemic activity of a polysaccharide extract from Fucus vesiculosus L.  Phytother Res. 1996;  10 647-650
• 24 Allain C C, Poon L C, Chan C S G, Richmond W, Fu P C. Enzymatic determination of total serum cholesterol.  Clin Chem. 1974;  20 470-475
• 25 McGowan M W, Artiss J D, Strandbergh D R, Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides.  Clin Chem. 1983;  29 538-542
• 26 Kurooka S, Okamoto S, Hashimoto M. A novel and simple colorimetric assay for human serum lipase.  J Biochem. 1977;  81 361-369
• 27 Harborne J B. Phenolic compounds. Harborne JB Phytochemical methods: a guide to modern techniques of plant analysis, 3rd edition. London; Chapman & Hall 1998: 40-106
• 28 Piyachaturawat P, Suwanampai P, Komaratat P, Chuncharunee A, Suksamrarn A. Effect of phloracetophenone on bile flow and biliary lipids in rats.  Hepatol Res. 1998;  12 198-206
• 29 Piyachaturawat P, Chai-ngam N, Chuncharunee A, Komaratat P, Suksamrarn A. Choleretic activity of phloracetophenone in rats: structure-function studies using acetophenone analogues.  Eur J Pharmacol. 2000;  387 221-227
• 30 Piyachaturawat P, Tubtim C, Chuncharunee A, Komaratat P, Suksamrarn A. Evaluation of the acute and subacute toxicity of a choleretic phloracetophenone in experimental animals.  Toxicol Lett. 2002;  129 123-132
• 31 Piyachaturawat P, Srivoraphan P, Chuncharunee A, Komaratat P, Suksamrarn A. Cholesterol lowering effects of a choleretic phloracetophenone in hypercholesterolemic hamsters.  Eur J Pharmacol. 2002;  439 141-147
• 32 Ito H, Nakasuga K, Ohshima A, Sakai Y, Maruyama T, Kaji Y, Harada M, Jingu S, Sakamoto M. Excess accumulation of body fat is related to dyslipidemia in normal-weight subjects.  Int J Obes Relat Metab Disord. 2004;  28 242-247
• 33 MacBride P. Triglycerides and risk for coronary artery disease.  Curr Atheroscler Rep. 2008;  10 386-390
• 34 Garattini S, Paoletti R. Drugs affecting lipid metabolism. Amsterdam; Elsevier 1961: 144
• 35 Pedrosa R C, Meyre-Silva C, Cechinel-Filho V, Benassi J C, Oliveira L F S, Zancanaro V, Dal Magro J, Yunes R A. Hypolipidaemic activity of methanol extract of Aleurites moluccana.  Phytother Res. 2002;  16 765-768
• 36 Amrani S, Harnafi H, Bouanani N E H, Aziz M, Caid H S, Manfredini S, Besco E, Napolitano M, Bravo E. Hypolipidaemic activity of aqueous Ocimum basilicum extract in acute hyperlipidaemia induced by triton WR-1339 in rats and its antioxidant property.  Phytother Res. 2006;  20 1040-1045
• 37 Ueshima K, Akihisa-Umeno H, Nagayoshi A, Takakura S, Matsuo M, Mutoh S. A gastrointestinal lipase inhibitor reduces progression of atherosclerosis in mice fed a western-type diet.  Eur J Pharmacol. 2004;  501 137-142
• 38 Martins F, Noso T M, Porto V B, Curiel A, Gambero A, Bastos D H M, Ribeiro M L, Carvalho P O. Maté tea inhibits in vitro pancreatic lipase activity and has hypolipidemic effect on high-fat-diet-induced obese mice.  Obesity. 2010;  18 42-47
• 39 Schieffer B, Drexler H. Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, angiotensin-converting enzyme inhibitors, cyclooxygenase-2 inhibitors, and aspirin in anti-inflammatory and immunomodulatory treatment of cardiovascular diseases.  Am J Cardiol. 2003;  91 12H-18H
• 40 Schiavo M, Lunardelli A, Oliveira J R. Influência da dieta na concentração sérica de triglicerídeos.  J Bras Patol Med Lab. 2003;  39 283-288
• 41 McNeely W, Benfield P. Orlistat.  Drugs. 1998;  56 241-249
• 42 Ballinger A, Peikin S R. Orlistat: its current status as an antiobesity drug.  Eur J Pharmacol. 2002;  440 109-117
• 43 Reitsma J B, Cabezas M C, de Bruin T W, Erkelens D W. Relationship between improved postprandial lipemia and low-density lipoprotein metabolism during treatment with tetrahydrolipstatin, a pancreatic lipase inhibitor.  Metabolism. 1994;  43 293-298
• 44 Ellrichmann M, Kapelle M, Ritter P R, Holst J J, Herzig K H, Schmidt W E, Schmitz F, Meier J J. Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations.  J Clin Endocrinol Metab. 2008;  93 3995-3998
• 45 Hsieh C J, Wang P W, Liu R T, Tung S C, Chien W Y, Chen J F, Chen C H, Kuo M C, Hu Y H. Orlistat for obesity: benefits beyond weight loss.  Diabetes Res Clin Pract. 2005;  67 78-83
• 46 Birari R B, Bhutani K K. Pancreatic lipase inhibitors from natural sources: unexplored potential.  Drug Discov Today. 2007;  12 879-889