In the Search of the Magic Bullet …
2010; Elsevier BV; Volume: 139; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2010.09.025
ISSN1528-0012
Autores Tópico(s)Genomics, phytochemicals, and oxidative stress
ResumoSee “Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach,” by Kalthoff S, Ehmer U, Freiberg N, et al, on page 1699.Coffee is one of the most popular beverages in the world—perhaps because it's so versatile. From simple espresso and filter coffee, to more complex preparations like cappuccino, this caffeinated drink can be as simple or as complicated as you want it to be. North Americans drink on average 3.1 cups of coffee every day.1Caffeine NationCBS Sunday Morning.2003Google Scholar, 2Coffee Drinking Trends Survey: National Coffee Association2000Google Scholar Although its distinct flavor and aroma has captured the hearts of billions of people worldwide, many still avoid the caffeinated version of this drink because of its frequently proclaimed bad effects on health such as gastric ulcers or arterial hypertension. However, more and more published studies reveal that in moderation, a few cups of coffee per day can even have beneficial health implications, in particular in regard to the liver.In 2 major pioneering studies from the National Institutes of Health that were published in this journal in 2005, Ruhl and Everhart3Ruhl C.E. Everhart J.E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States.Gastroenterology. 2005; 129: 1928-1936Abstract Full Text Full Text PDF Scopus (173) Google Scholar, 4Ruhl 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: 24-32Abstract Full Text Full Text PDF Scopus (200) Google Scholar examined patients with liver injury of different etiologies and using unadjusted logistic regression and multivariate analyses, they calculated a lower risk of alanine aminotransferase (ALT) elevation with increasing coffee (P = .001) and caffeine (P = .001) consumption. Across all the liver disease risk factors examined, those patients with highest caffeine intake had only one third the risk of ALT elevations compared to those patients with the lowest consumption [odds ratio [OR], 0.31; 95% confidence interval [CI], 0.16–0.61].Despite such strong epidemiologic evidence, the underlying molecular mechanisms remain elusive. One reason may be that coffee contains a vast number of different compounds, including caffeine, as well as the coffee oils kahweol and cafestol, any of which may be responsible for the effects described in clinical studies. One possibly hepatoprotective molecular mechanism was proposed recently by our group, which is based on the fact that caffeine and other methylxanthines are well known to elevate intracellular cyclic adenosine monophosphate levels by inhibiting phosphodiesterase activity.5Belibi F.A. Wallace D.P. Yamaguchi T. et al.The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2002; 13: 2723-2729Google Scholar By doing so, we could show that caffeine is able to induce proteasomal degradation of the profibrogenic transforming growth factor (TGF)-β signal mediator Smad2 and to inhibit also the phosphorylation of and even partially degrade total Smad3 protein, which is allosterically bound to the type 1 receptor in the Smad3/Sara (Smad anchor for receptor activation)/TGF-β type 1 receptor kinase complex upon receptor activation by the cytokine (Figure 1) .6Gressner O.A. Lahme B. Rehbein K. et al.Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways.J Hepatol. 2008; 49: 758-767Abstract Full Text Full Text PDF Scopus (108) Google ScholarIn turn, these molecular biological results find clinical parallels in a very recent National Institutes of Health study showing that caffeine consumption, particularly from regular coffee, above a threshold of about 2 coffee-cup equivalents per day, was associated with less severe hepatic fibrosis in patients suffering from chronic hepatitis C virus infection.7Modi A.A. Feld J.J. Park Y. et al.Increased caffeine consumption is associated with reduced hepatic fibrosis.Hepatology. 2010; 51: 201-209Google Scholar The work by Ruhl and Everhart3Ruhl C.E. Everhart J.E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States.Gastroenterology. 2005; 129: 1928-1936Abstract Full Text Full Text PDF Scopus (173) Google Scholar, 4Ruhl 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: 24-32Abstract Full Text Full Text PDF Scopus (200) Google Scholar reported already that, after multivariate analysis, the relationship between caffeine and reduced serum ALT levels was of greater significance than that for coffee alone (coffee, P = .034; caffeine, P < .001). Furthermore, Sharp and Benowitz8Sharp D.S. Benowitz N.L. Re: “Alcohol, smoking, coffee, and cirrhosis” and “coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan”.Am J Epidemiol. 1995; 141: 480-482Google Scholar demonstrated that caffeine intake and serum caffeine levels were associated with lower levels of GGT and, in animal studies, caffeine has been shown to inhibit chemically induced hepatic carcinogenesis.9Hosaka S. Kawa S. Aoki Y. et al.Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene.Food Chem Toxicol. 2001; 39: 557-561Google Scholar, 10Tanaka T. Nishikawa A. Shima H. et al.Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.Basic Life Sci. 1990; 52: 429-440Google ScholarClinically relevant hepatoprotective effects are not restricted to caffeine, but are present also for the coffee-specific diterpenes kahweol and cafestol.11Lee K.J. Choi J.H. Jeong H.G. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice.Food Chem Toxicol. 2007; 45: 2118-2125Google Scholar, 12Gross G. Jaccaud E. Huggett A.C. Analysis of the content of the diterpenes cafestol and kahweol in coffee brews.Food Chem Toxicol. 1997; 35: 547-554Google Scholar Just as for caffeine, the underlying mechanisms are not fully understood, but it seems that inhibition of bioactivation and stimulation of detoxification are central events. In the kahweol- and cafestol-induced signal transduction, activation of the cis-acting antioxidant-responsive-element (ARE) sequence, which was identified on the promoter of several genes involved in detoxification processes (including those encoding phase II detoxifying enzymes and antioxidant proteins13Hayes J.D. Ellis E.M. Neal G.E. et al.Cellular response to cancer chemopreventive agents: contribution of the antioxidant responsive element to the adaptive response to oxidative and chemical stress.Biochem Soc Symp. 1999; 64: 141-168Google Scholar), and of Nrf2 (nuclear factor erythroid 2-related factor)14McMahon M. Itoh K. Yamamoto M. et al.The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes.Cancer Res. 2001; 61: 3299-3307Google Scholar seem to play key roles. Under physiologic conditions, Nrf2 activation is repressed by its binding to the cytoskeleton, and to a cytosolic protein known as Keap1 (Kelch-like ECH-associated protein 1; a cysteine-rich protein) in a redox-sensitive manner.15Kobayashi M. Itoh K. Suzuki T. et al.Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system.Genes Cells. 2002; 7: 807-820Google Scholar This Keap1/Nrf2 complex promotes permanent Nrf2 degradation by the proteasome.16Dhakshinamoorthy S. Jaiswal A.K. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene.Oncogene. 2001; 20: 3906-3917Google Scholar, 17Itoh K. Wakabayashi N. Katoh Y. et al.Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.Genes Dev. 1999; 13: 76-86Google ScholarKahweol and cafestol disrupts the cytoplasmic Keap1/Nrf2 complex through thiol modification of cysteine residues in Keap1, and the dissociation of these proteins in the cytoplasm is followed by transportation of Nrf2 to the nucleus where it transcriptionally activates ARE-dependent genes (Figure 1).18Dinkova-Kostova A.T. Holtzclaw W.D. Cole R.N. et al.Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants.Proc Natl Acad Sci U S A. 2002; 99: 11908-11913Google Scholar However, kahweol and cafestol are only present in small amounts in filtered coffee; therefore, it is unlikely that coffee's hepatoprotective effects may be exclusively attributed to these constituents. The reports showing that caffeine, in addition to its effects on TGF-β signaling, is able to phosphorylate and release Nrf2 through activation of the MAPK/ERK signal pathway. This then permits Nrf2 translocation to the nucleus where it transcriptionally activates ARE-dependent genes, and provides an additional mechanism of action.19Okano J. Nagahara T. Matsumoto K. et al.Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway.Basic Clin Pharmacol Toxicol. 2008; 102: 543-551Google ScholarIn this issue of Gastroenterology, Kalthoff et al20Kalthoff S. Ehmer W. Freiberg N. et al.Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach.Gastroenterology. 2010; 139: 1699-1710Google Scholar add to these discoveries and sort out 1 specific target that is involved in hepatic detoxification processes and whose family of enzymes is known to be activated by coffee: uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase [UGT]) 1A. UGTs are microsomal membrane-bound proteins that catalyze the transfer of a glucuronate group of uridine diphosphoglucuronate (UDPGA, a co-substrate) to the functional group of specific substrates, thereby conferring polarity to the substrate which can then be easily excreted in the bile. Glucuronidation is the major pathway in hepatic phase II metabolism.21King C.D. Rios G.R. Green M.D. et al.UDP-glucuronosyltransferases.Curr Drug Metab. 2000; 1: 143-161Google ScholarThe principal objective of Kalthoff et al's study is to examine UGT 1A gene regulation in the presence and absence of standard preparations of regular, metal- and paper-filtered, decaffeinated, and instant coffee, green and black tea, and cocoa as well as coffee diterpenes and methylxanthines using sophisticated in vitro and in vivo experimental techniques. The outcomes are both expected and surprising: (I) UGT 1A genes are highly inducible in vitro and in vivo by coffee via coordinated Nrf2/ARE signal transduction—a result that can be expected based upon the above discussion. However, Kalthoff et al contend that (II) UGT 1A gene induction by coffee takes place independently from the caffeine content, and independent of cafestol or kahweol. This is both novel and surprising.The concept by Kalthoff et al that coffee consumption leads to an activation of hepatic phase II detoxification processes is, not new per se—the induction of ARE sequence containing genes, in particular of those involved in hepatic phase II detoxification processes, has been described previously.22Lam L.K. Sparnins V.L. Wattenberg L.W. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse.Cancer Res. 1982; 42: 1193-1198Google Scholar, 23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar However, the ingredients therein that were invoked to be responsible for this phenomenon so far were primarily the 2 coffee specific diterpenes, namely kahweol and cafestol. Lam et al22Lam L.K. Sparnins V.L. Wattenberg L.W. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse.Cancer Res. 1982; 42: 1193-1198Google Scholar and Huber et al23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar described kahweol and cafestol as strong inductors of the hepatic activities of several phase II xenobiotic metabolizing enzymes, including UGT (also addressed by Kalthoff et al), and glutathione S-transferase (GST). Furthermore, the effects of kahweol and cafestol on the expression of various GST subunits were studied in the rat.23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar, 24Cavin C. Holzhauser D. Constable A. et al.The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism.Carcinogenesis. 1998; 19: 1369-1375Google Scholar Particularly striking was an early and strictly dose-dependent induction of the GST Pi subunit Yp and the alpha subunit Yc2 (rGST A5) expression in the liver after long-term treatment with a kahweol- and cafestol-containing diet. Moreover, it was shown that the increased expression is dependent upon a continuous presence of kahweol and cafestol in the diet and that it is easily reversible after removal of kahweol and cafestol.24Cavin C. Holzhauser D. Constable A. et al.The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism.Carcinogenesis. 1998; 19: 1369-1375Google Scholar Consistent with this, levels of overall GST activity increased 2- to 3-fold during a 10-day dietary exposure to 2000 ppm kahweol and cafestol, but returned to pretreatment levels only 10 days after clearing the diet from the 2 diterpenes.23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google ScholarSo what is it that makes the study of Kalthoff's group so novel and interesting? It is the fact that they are the first to show that the hepatic phase II detoxification processes known to be triggered by coffee do not necessarily require the presence of, or are not exclusively mediated by, caffeine, kahweol, and cafestol, or methylxanthines, although the induction of UGT 1A is also mediated by the Nrf2/ARE signaling pathway. As a result, Kalthoff et al oppose common beliefs and triggers yet another search for new hepatoprotective substances in this complex “blend” of a vast number of different chemicals, tastefully prepared as cappuccino, latte macchiato, or espresso. Buon divertimento!. See “Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach,” by Kalthoff S, Ehmer U, Freiberg N, et al, on page 1699. See “Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach,” by Kalthoff S, Ehmer U, Freiberg N, et al, on page 1699. See “Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach,” by Kalthoff S, Ehmer U, Freiberg N, et al, on page 1699. Coffee is one of the most popular beverages in the world—perhaps because it's so versatile. From simple espresso and filter coffee, to more complex preparations like cappuccino, this caffeinated drink can be as simple or as complicated as you want it to be. North Americans drink on average 3.1 cups of coffee every day.1Caffeine NationCBS Sunday Morning.2003Google Scholar, 2Coffee Drinking Trends Survey: National Coffee Association2000Google Scholar Although its distinct flavor and aroma has captured the hearts of billions of people worldwide, many still avoid the caffeinated version of this drink because of its frequently proclaimed bad effects on health such as gastric ulcers or arterial hypertension. However, more and more published studies reveal that in moderation, a few cups of coffee per day can even have beneficial health implications, in particular in regard to the liver. In 2 major pioneering studies from the National Institutes of Health that were published in this journal in 2005, Ruhl and Everhart3Ruhl C.E. Everhart J.E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States.Gastroenterology. 2005; 129: 1928-1936Abstract Full Text Full Text PDF Scopus (173) Google Scholar, 4Ruhl 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: 24-32Abstract Full Text Full Text PDF Scopus (200) Google Scholar examined patients with liver injury of different etiologies and using unadjusted logistic regression and multivariate analyses, they calculated a lower risk of alanine aminotransferase (ALT) elevation with increasing coffee (P = .001) and caffeine (P = .001) consumption. Across all the liver disease risk factors examined, those patients with highest caffeine intake had only one third the risk of ALT elevations compared to those patients with the lowest consumption [odds ratio [OR], 0.31; 95% confidence interval [CI], 0.16–0.61]. Despite such strong epidemiologic evidence, the underlying molecular mechanisms remain elusive. One reason may be that coffee contains a vast number of different compounds, including caffeine, as well as the coffee oils kahweol and cafestol, any of which may be responsible for the effects described in clinical studies. One possibly hepatoprotective molecular mechanism was proposed recently by our group, which is based on the fact that caffeine and other methylxanthines are well known to elevate intracellular cyclic adenosine monophosphate levels by inhibiting phosphodiesterase activity.5Belibi F.A. Wallace D.P. Yamaguchi T. et al.The effect of caffeine on renal epithelial cells from patients with autosomal dominant polycystic kidney disease.J Am Soc Nephrol. 2002; 13: 2723-2729Google Scholar By doing so, we could show that caffeine is able to induce proteasomal degradation of the profibrogenic transforming growth factor (TGF)-β signal mediator Smad2 and to inhibit also the phosphorylation of and even partially degrade total Smad3 protein, which is allosterically bound to the type 1 receptor in the Smad3/Sara (Smad anchor for receptor activation)/TGF-β type 1 receptor kinase complex upon receptor activation by the cytokine (Figure 1) .6Gressner O.A. Lahme B. Rehbein K. et al.Pharmacological application of caffeine inhibits TGF-beta-stimulated connective tissue growth factor expression in hepatocytes via PPARgamma and SMAD2/3-dependent pathways.J Hepatol. 2008; 49: 758-767Abstract Full Text Full Text PDF Scopus (108) Google Scholar In turn, these molecular biological results find clinical parallels in a very recent National Institutes of Health study showing that caffeine consumption, particularly from regular coffee, above a threshold of about 2 coffee-cup equivalents per day, was associated with less severe hepatic fibrosis in patients suffering from chronic hepatitis C virus infection.7Modi A.A. Feld J.J. Park Y. et al.Increased caffeine consumption is associated with reduced hepatic fibrosis.Hepatology. 2010; 51: 201-209Google Scholar The work by Ruhl and Everhart3Ruhl C.E. Everhart J.E. Coffee and tea consumption are associated with a lower incidence of chronic liver disease in the United States.Gastroenterology. 2005; 129: 1928-1936Abstract Full Text Full Text PDF Scopus (173) Google Scholar, 4Ruhl 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: 24-32Abstract Full Text Full Text PDF Scopus (200) Google Scholar reported already that, after multivariate analysis, the relationship between caffeine and reduced serum ALT levels was of greater significance than that for coffee alone (coffee, P = .034; caffeine, P < .001). Furthermore, Sharp and Benowitz8Sharp D.S. Benowitz N.L. Re: “Alcohol, smoking, coffee, and cirrhosis” and “coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan”.Am J Epidemiol. 1995; 141: 480-482Google Scholar demonstrated that caffeine intake and serum caffeine levels were associated with lower levels of GGT and, in animal studies, caffeine has been shown to inhibit chemically induced hepatic carcinogenesis.9Hosaka S. Kawa S. Aoki Y. et al.Hepatocarcinogenesis inhibition by caffeine in ACI rats treated with 2-acetylaminofluorene.Food Chem Toxicol. 2001; 39: 557-561Google Scholar, 10Tanaka T. Nishikawa A. Shima H. et al.Inhibitory effects of chlorogenic acid, reserpine, polyprenoic acid (E-5166), or coffee on hepatocarcinogenesis in rats and hamsters.Basic Life Sci. 1990; 52: 429-440Google Scholar Clinically relevant hepatoprotective effects are not restricted to caffeine, but are present also for the coffee-specific diterpenes kahweol and cafestol.11Lee K.J. Choi J.H. Jeong H.G. Hepatoprotective and antioxidant effects of the coffee diterpenes kahweol and cafestol on carbon tetrachloride-induced liver damage in mice.Food Chem Toxicol. 2007; 45: 2118-2125Google Scholar, 12Gross G. Jaccaud E. Huggett A.C. Analysis of the content of the diterpenes cafestol and kahweol in coffee brews.Food Chem Toxicol. 1997; 35: 547-554Google Scholar Just as for caffeine, the underlying mechanisms are not fully understood, but it seems that inhibition of bioactivation and stimulation of detoxification are central events. In the kahweol- and cafestol-induced signal transduction, activation of the cis-acting antioxidant-responsive-element (ARE) sequence, which was identified on the promoter of several genes involved in detoxification processes (including those encoding phase II detoxifying enzymes and antioxidant proteins13Hayes J.D. Ellis E.M. Neal G.E. et al.Cellular response to cancer chemopreventive agents: contribution of the antioxidant responsive element to the adaptive response to oxidative and chemical stress.Biochem Soc Symp. 1999; 64: 141-168Google Scholar), and of Nrf2 (nuclear factor erythroid 2-related factor)14McMahon M. Itoh K. Yamamoto M. et al.The Cap'n'Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes.Cancer Res. 2001; 61: 3299-3307Google Scholar seem to play key roles. Under physiologic conditions, Nrf2 activation is repressed by its binding to the cytoskeleton, and to a cytosolic protein known as Keap1 (Kelch-like ECH-associated protein 1; a cysteine-rich protein) in a redox-sensitive manner.15Kobayashi M. Itoh K. Suzuki T. et al.Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system.Genes Cells. 2002; 7: 807-820Google Scholar This Keap1/Nrf2 complex promotes permanent Nrf2 degradation by the proteasome.16Dhakshinamoorthy S. Jaiswal A.K. Functional characterization and role of INrf2 in antioxidant response element-mediated expression and antioxidant induction of NAD(P)H:quinone oxidoreductase1 gene.Oncogene. 2001; 20: 3906-3917Google Scholar, 17Itoh K. Wakabayashi N. Katoh Y. et al.Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain.Genes Dev. 1999; 13: 76-86Google Scholar Kahweol and cafestol disrupts the cytoplasmic Keap1/Nrf2 complex through thiol modification of cysteine residues in Keap1, and the dissociation of these proteins in the cytoplasm is followed by transportation of Nrf2 to the nucleus where it transcriptionally activates ARE-dependent genes (Figure 1).18Dinkova-Kostova A.T. Holtzclaw W.D. Cole R.N. et al.Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants.Proc Natl Acad Sci U S A. 2002; 99: 11908-11913Google Scholar However, kahweol and cafestol are only present in small amounts in filtered coffee; therefore, it is unlikely that coffee's hepatoprotective effects may be exclusively attributed to these constituents. The reports showing that caffeine, in addition to its effects on TGF-β signaling, is able to phosphorylate and release Nrf2 through activation of the MAPK/ERK signal pathway. This then permits Nrf2 translocation to the nucleus where it transcriptionally activates ARE-dependent genes, and provides an additional mechanism of action.19Okano J. Nagahara T. Matsumoto K. et al.Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway.Basic Clin Pharmacol Toxicol. 2008; 102: 543-551Google Scholar In this issue of Gastroenterology, Kalthoff et al20Kalthoff S. Ehmer W. Freiberg N. et al.Coffee induces expression of glucuronosyltransferases by the aryl hydrocarbon receptor and Nrf2 in liver and stomach.Gastroenterology. 2010; 139: 1699-1710Google Scholar add to these discoveries and sort out 1 specific target that is involved in hepatic detoxification processes and whose family of enzymes is known to be activated by coffee: uridine 5′-diphospho-glucuronosyltransferase (UDP-glucuronosyltransferase [UGT]) 1A. UGTs are microsomal membrane-bound proteins that catalyze the transfer of a glucuronate group of uridine diphosphoglucuronate (UDPGA, a co-substrate) to the functional group of specific substrates, thereby conferring polarity to the substrate which can then be easily excreted in the bile. Glucuronidation is the major pathway in hepatic phase II metabolism.21King C.D. Rios G.R. Green M.D. et al.UDP-glucuronosyltransferases.Curr Drug Metab. 2000; 1: 143-161Google Scholar The principal objective of Kalthoff et al's study is to examine UGT 1A gene regulation in the presence and absence of standard preparations of regular, metal- and paper-filtered, decaffeinated, and instant coffee, green and black tea, and cocoa as well as coffee diterpenes and methylxanthines using sophisticated in vitro and in vivo experimental techniques. The outcomes are both expected and surprising: (I) UGT 1A genes are highly inducible in vitro and in vivo by coffee via coordinated Nrf2/ARE signal transduction—a result that can be expected based upon the above discussion. However, Kalthoff et al contend that (II) UGT 1A gene induction by coffee takes place independently from the caffeine content, and independent of cafestol or kahweol. This is both novel and surprising. The concept by Kalthoff et al that coffee consumption leads to an activation of hepatic phase II detoxification processes is, not new per se—the induction of ARE sequence containing genes, in particular of those involved in hepatic phase II detoxification processes, has been described previously.22Lam L.K. Sparnins V.L. Wattenberg L.W. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse.Cancer Res. 1982; 42: 1193-1198Google Scholar, 23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar However, the ingredients therein that were invoked to be responsible for this phenomenon so far were primarily the 2 coffee specific diterpenes, namely kahweol and cafestol. Lam et al22Lam L.K. Sparnins V.L. Wattenberg L.W. Isolation and identification of kahweol palmitate and cafestol palmitate as active constituents of green coffee beans that enhance glutathione S-transferase activity in the mouse.Cancer Res. 1982; 42: 1193-1198Google Scholar and Huber et al23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar described kahweol and cafestol as strong inductors of the hepatic activities of several phase II xenobiotic metabolizing enzymes, including UGT (also addressed by Kalthoff et al), and glutathione S-transferase (GST). Furthermore, the effects of kahweol and cafestol on the expression of various GST subunits were studied in the rat.23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar, 24Cavin C. Holzhauser D. Constable A. et al.The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism.Carcinogenesis. 1998; 19: 1369-1375Google Scholar Particularly striking was an early and strictly dose-dependent induction of the GST Pi subunit Yp and the alpha subunit Yc2 (rGST A5) expression in the liver after long-term treatment with a kahweol- and cafestol-containing diet. Moreover, it was shown that the increased expression is dependent upon a continuous presence of kahweol and cafestol in the diet and that it is easily reversible after removal of kahweol and cafestol.24Cavin C. Holzhauser D. Constable A. et al.The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity through a dual mechanism.Carcinogenesis. 1998; 19: 1369-1375Google Scholar Consistent with this, levels of overall GST activity increased 2- to 3-fold during a 10-day dietary exposure to 2000 ppm kahweol and cafestol, but returned to pretreatment levels only 10 days after clearing the diet from the 2 diterpenes.23Huber W.W. Prustomersky S. Delbanco E. et al.Enhancement of the chemoprotective enzymes glucuronosyl transferase and glutathione transferase in specific organs of the rat by the coffee components kahweol and cafestol.Arch Toxicol. 2002; 76: 209-217Google Scholar So what is it that makes the study of Kalthoff's group so novel and interesting? It is the fact that they are the first to show that the hepatic phase II detoxification processes known to be triggered by coffee do not necessarily require the presence of, or are not exclusively mediated by, caffeine, kahweol, and cafestol, or methylxanthines, although the induction of UGT 1A is also mediated by the Nrf2/ARE signaling pathway. As a result, Kalthoff et al oppose common beliefs and triggers yet another search for new hepatoprotective substances in this complex “blend” of a vast number of different chemicals, tastefully prepared as cappuccino, latte macchiato, or espresso. Buon divertimento!. Coffee Induces Expression of Glucuronosyltransferases by the Aryl Hydrocarbon Receptor and Nrf2 in Liver and StomachGastroenterologyVol. 139Issue 5PreviewCoffee is one of the most widely consumed beverages worldwide. Epidemiologic data indicate that coffee consumption protects against the progression of chronic liver disease and development of hepatocellular carcinoma and diabetes, but the mechanisms are not clear. UDP glucuronosyltransferases (UGT1A) are proteins with indirect antioxidant, cytoprotective, and genoprotective capabilities; we examined UGT1A regulation in response to coffee in cultured cells and mice. Full-Text PDF
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