Methylxanthine Drugs Are Human Pancreatic Lipase Inhibitors
Methylxanthines such as caffeine, theobromine and theophylline are intensively consumed as food components by large proportion of human population all over the world. This class of compounds show various biological activities and have been found to act as broad specificity inhibitors towards numerous enzymes. However, their action on digestive enzymes have not been yet investigated. In this paper we aimed to evaluate the effects of methylxanthines on the human pancreatic lipase activity in vitro. Emulsions of short- and long-chain triglycerides (tributyrin and tripalmitate, respectively) were used as substrates. The concentrations of methylxanthines in the reaction mixtures covered the range between 0.015 mmol/L to 15 mmol/L. We demonstrated that all three tested substances, caffeine, theophylline and theobromine inhibited the hydrolysis of tributyrin and tripalmitate catalysed by human pancreatic lipase in dose-dependent fashion. The highest lipase inhibition ratios during tripalmitate and tributyrin hydrolysis were 25.74% and 79.54% respectively in the presence of caffeine, 29.89% and 62.79% respectively with theophylline and 21.08% and 67.74% respectively in the presence of theobromine. All the tested methylxanthines exert stronger inhibition in the short-chain triglyceride lipolysis comparing to long-chain substrates. Their mechanism of action involves most likely the interaction with enzyme protein but not substrate emulgation. In case of tripalmitate lipolysis all the methylxanthines showed mixed type of inhibition. Interestingly, during tributyrin lipolysis theophylline behaved as classical noncompetitive inhibitor.
If the inline PDF is not rendering correctly, you can download the PDF file here.
Baselt R. C. Disposition of Toxic Drugs and Chemicals in Man. 2004 7th ed. Biomedical Publications. Foster City CA pp. 157-159.
Brockman H. L. Kinetic behaviour of the pancreatic lipase-colipase-lipid system. Biochimie 2000 82 987-995.
Caudle A. G. Bell L. N. Caffeine and theobromine contents of ready-to-eat chocolate cereals. Research and Professional Briefs J. Am. Diet. Assoc. 2000 100 690-692.
Colin D. Y. Deprez-Beauclair P. Allouche M. Brasseur R. Kerfelec B. Exploring the activity site cavity of human pancreatic lipase. Biochem. Biophys. Res. Commun. 2008 370 394-398.
Eteng M. U. Ettarh R. R. Comparative effects of theobromine and cocoa extract on lipid profile in rats. Nutr. Res. 2000 20 1513-1517.
Fish B. C. Thompson L. U. Lectin-tanin interactions and influence on pancreatic amylase activity and starch digestibility. J. Agric. Food Chem. 1991 39 727-731.
Freie A. B. Ferrato F. Carriare F. Lowe M. E. Val-407 and Ile-408 in the beta 5'-loop of pancreatic lipase mediate lipase-colipase interactions in the presence of bile salt micelles. J. Biol. Chem. 2006 281 7793-7800.
Greenway F. K. de Jonge L. Blanchard D. Frisard M. Smith S. R. Effect of dietary herbal supplement containing caffeine and ephedra on weight metabolic rate and body composition. Obesity Res. 2004 12 1152-1157.
Grosso L. M. Bracken M. B. Caffeine metabolism genetics and perinatal outcomes: A review of exposure assessment considerations during pregnancy. Ann. Epidemiol. 2005 15 460-466.
Gu Y. Hurst W. J. Stuart D. A. Lambert J. D. Inhibition of key digestive enzymes by cocoa extracts and procyanidins. J. Agric. Food Chem. 2011 59 5305-5311.
Haller C. A. Jacob P. Benowitz N. L. Enhanced stimulant and metabolic effects of combined ephedrine and caffeine. Clin. Pharmacol. Ther. 2004 75 259-273.
Harland B. F. Caffeine and nutrition. Nutrition 2000 16 522-526.
Mandel H. G. Update on caffeine consumption disposition and action. Food Chem. Toxicol. 2002 40 1231-1234.
Miled N. Canaan S. Dupuis L. Roussel A. Riviere M. Carriere F. de Caro A. Cambillau C. Verger R. Digestive lipases: From three-dimensional structure to physiology. Biochimie 2000 82 973-986.
Møller S. E. Larsen F. Pitsiu M. Rolan P. E. Effect of citalopram on plasma levels of oral theophylline. Clin. Ther. 2000 22 1494-1501.
Mun S. Decker E. A. McClements D. J. Influence of emulsifier type on in vitro digestibility of lipid droplets by pancreatic lipase. Food Res. Int. 2007 40 770-781.
Nafisi S. Shamloo D. S. Mohajerani N. Omidi A. A comparative study of caffeine and theophylline binding to Mg(II) and Ca(II) ions: studied by FTIR and UV spectroscopic methods. J. Mol. Struc. 2002 608 1-7.
Näher G. Lipase-titrimetric assay. 1974 in: Methods of Enzymatic Analysis vol. 2 (ed. H. U. Bergmeyer). Academic Press pp. 814-818.
Papaioannou T. G. Karatzi K. Karatzis E. Papamichael C. Lekakis J. P. Acute effects of caffeine on arterial stiffness wave reflections and central aortic pressures. Am. J. Hypertens. 2005 18 129-136.
Ranaldi S. Belle V. Woudstra M. Bourgas R. Guigliarelli B. Roche P. Vezin H. Carriere F. Fournel A. Amplitude of pancreatic lipase lid opening in solution and identification of spin label conformational subensembles by combining continuous wave and pulsed EPR spectroscopy and molecular dynamics. Biochemistry 2010 49 2140-2149.
Rao F. V. Andersen O. A. Vora K. D. de Martino J. A. van Alten D. M. F. Methylxanthine drugs are chitinase inhibitors: Investigation of inhibition and binding models. Chem. Biol. 2005 12 973-980.
Ruhl C. E. Everhart J. E. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology 2005 128 24-32.
Steiner J. M. Williams D. A. Purification of classical pancreatic lipase from dog pancreas. Biochimie 2002 84 1245-1253.
Sugawara M. Mochizuki T. Takekuma Y. Miyazaki K. Structure-affinity relationship in the interactions of human organic anion transporter with caffeine theophylline theobromine and their metabolites. Biochem. Biophys. Acta 2005 1714 85-92.
Westerterp-Plantenga M. Diepvens K. Joosen A. M. Berube-Parent S. Tremblay A. Metabolic effects of spices teas and caffeine. Physiol. Behav. 2006 89 85-91.
Winkler F. K. D'Arcy A. Hunziker W. Structure of human pancreatic lipase. Nature 1990 343 771-774.
WHO World Health Organization International. Evaluation of certain food additives and contaminants. 44th Report of the Join FAO/WHO Expert Committee on Food Additives. WHO Expert Committee on Biological Standardization. 1995 859 5-8.