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1. Microbiology

Author

Figura, N., Owen, R. J., Desai, M., Bayeli, P. F., HGregorio, L. Di, Russi, M., Musmanno, R. A., Hawtin, P. R., Sharpstone, D., Hayes, L., Nøorgaard, A., Nielsen, H., Andersen, L. P., Geis, G., Leying, H., Suerbaum, S., Opferkuch, W., Tonokatsu, Y., Hayashi, T., Fukuda, Y., Yamamoto, I., Takami, S., Tamura, T., Shimoyama, T., Lopez-Brea, M., Martin, E., C.Sanz, J., Alonso, M., Alarcon, T., Michetti, P., Porta, N., Racine, L., P.Kraehenbuhl, J., L.Blum, A., Cardeñoso, L., Moran, A. P., Muotiala, A., Pyhälä, L., Kosunen, T. U., Helander, I. M., Roine, R. P., Salmela, K. S., Höök-Nikanne, J., Salaspuro, M., Daw, M. A., Xia, H. X., O’Morain, C., Lelwala-Guruge, J., Ascencio, F., Ljungh, Å., Wadström, T., Ringnér, Martina, Valkonen, Kaija, Paulsson, Marianne, Ljungh, Åsa, Wadström, Torkel, Guldvog, I., Tannaes, T., Bukholm, G., Grav, H., Corinaldesi, R., Tucci, A., Stanghellini, V., Gasperoni, S., Varoli, O., Paparo, G. F., Gaetani, M., Cioffi, G., Barbara, L., Husson, M. O., Legrand, D., Mazurier, J., Caron, C., Leclerc, H., Spik, G., English, L., Keane, C. T., O’Morain, C. A., Fox, J. G., Correa, P., Taylor, N. S., Fatela, N., Melo Cristino, J., Monteiro, L., Ramalho, F., Saragoça, A., Salgado, M.J, Mauch, F., Bode, G., Ditschuneit, H., Malfertheiner, P., Nilius, M., Pugliese, M., Moshkowitz, M., Gorea, A., Santo, M., Berger, S., Gilat, T., Belluzzi, A., Vaira, D., Campieri, M., Boschi, S., Gionchetti, P., Mulè, P., Brignola, C., Rizzello, F., Miglioli, M., Barbara, L., Lamouliatte, H., Brugmann, D., Cayla, R., H. Bernard, P., Mégraud, F., Quinton, A., Bär, W., Wagner, S., Glen-Calvo, E., Koopmann, H., Szentmihalyi, A., Radnai, Z., Molnar, Gy., Bálint, A., and Ihász, M.

Published
1992
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2. Abstract form for the Irish Journal of Medical Science v workshop on gastroduodenal pathology and Helicobacter pylori July 5th — 7th 1992 — Dublin, Ireland

Author

Logan, R. P. H., Gummett, P. A., Walker, M. M., Karim, Q. N., Baron, J. H., Misiewicz, J. J., Trieber, G., Walker, S., Klotz, U., Lozniewski, A., Weber, M., de Korwin, J. D., Floquet, J., Conroy, M. C., Burdin, J. C., Mannes, G. A., Bayerdörffer, E., Höchter, W., Weingart, J., Heldwein, W., Sommer, A., Müller-Lissner, S., Bomschein, W., Miehlke, S., Weinzierl, M., Ruckdeschel, G., von Wulffen, H., Köpcke, W., Stolte, M., Rune, S. J., Justesen, T., Hansen, J. M., Jensen, T. G., Eriksen, J., Thomsen, O. ø., Scheibel, J., Bonnevie, O., Bremmelgaard, A., Vilien, M., Knuhtsen, S., Elsborg, L., Hansen, J., Lauritsen, K., Wulff, H. R., Boixeda, D., Ballestero, S., Cantón, R., De Rafael, L., Martinm de Argila, C., Pozuelo, M. J., Sampedro, J., Baquero, F., Grigoriev, P. Ya., Isakov, V. A., Iakovenko, E. P., Hirschl, A. M., Brandstätter, G., Dragosics, B., Hentschel, E., Kundi, M., Rotter, M. L., Schütze, K., Taufer, M., Neri M, Susi D, Bovani I, Pindo R, Cuccurullo F., Coelho, L. G. V., Passos, M. C. F., Chausson, Y., Vieira, W. L. S., Castro, F. J., Franco, J. M. M., Fernandes, M. L. M., Castro, L. P., Jonas, C., De Koster, E., Van Gossum, M., Depierreux, M., Cheval, M., Deltenre, M., Schütz, E., Bethke, B., Lee, A., Hegedus, E., O’Rourke, J., Larsson, H., Sjöstedt, S., Veress, B., Nord, C. E., Sobala, G. M., George, R., Tompkins, D., Finlay, J., Manning, A., Sant, S., Xia, H. X., Daw, M., Gilvarry, J., Keane, C. T., O’Morain, C., Rubio, M. A., Hegarty, B., Blum, A. L., Sulser, E., Stadelmann, O., Munoz, N., Buiatti, E., Vivas, J., Oliver, W., Cano, E., Peraza, S., Castro, D., Sanchez, V., Andrade, O., Benz, M., Mendz, G. L., Hazell, S. L., Salmela, K. S., Roire, R. P., Hook-Nikanne, J., Kosunen, T. U., Salaspur, M., Luke, C. J., Reynolds, D. D. J., Penn, C. W., Bode, G., Mauch, F., Ditschuneit, H., Malfertheiner, P., Ferrero, Richard L., Agnes Labigne, Eaton, K. A., Krakowka, S., Mobley, H. L. T., Hu, Li-Tai, Foxall, P. A., Moran, A. P., Helander, I. M., Altman, C., Sobhani, I., Vissugaire, C., Migrant, M., Etienne, J. P., Sommi, P., Ricci, V., Fiocca, R., Cova, E., Figura, N., Romano, M., Ivey, K. J., Solcia, E., Ventura, U., Nilius, M., Schieffer, S., Hengels, K. J., Jablonowski, H., Strohmeyer, G., Cabrai, M. D., Barbosa, A. J. A., Lima Hr., G. F., Oliveira, C. A., Polak, J. M., Oderda, G., Villani, L., Altare, F., Morra, I., Miserendino, L., Ansaldi, N., Dixon, M. F., Wyatt, J. I., Axon, A. T. R., Beattie, S., Hamilton, H., Shabib, S., Cutz, E., Drumm, B., Sherman, P., Noach, L. A., Rolf, T., Bosma, N. B., Schwartz, M. P., Oosting, J., Rauws, E. A. J., Tytgat, G. N. J., Andrew, A., Nardone, G., d’Ormiento, F., Pontillo, M., Lobo, A. J., Uff, J. S., McNulty, C. N. M., Wilkinson, S. P., Suriani, R., Pallante, C., Ravizza, M., Galliano, D., Sallio, D., Malandrino, M., Oneglio, R., Colozza, M., Mazzucco, D., Gaia, E., Eidt, S., Vincent, P., Gottrand, F., Turck, D., Lecomte-Houcke, M., Leclerc, H., Bonvicini, F., Pretolani, S., Baraldini, M., Cilla, D., Baldinelli, S., Bazocchi, E., Acampora, P., Careddu, N., Brocchi, E., Gasbarrini, G., Joubert, M., Bazin, N., Thiaucourt, D., Protte, E., Gissler, C., Duprez, A., Merlin, P., Forestier, S., Labenz, J., Gyenes, E., Rühl, G. H., Börsch, G., Daskalopoulos, G., Carrick, J., Lian, R., Wagner, S., Bleck, J., Gebel, M., Bär, W., Manns, M., Lamouliatte, H., Bernard, P. H., Cayla, R., Vialette, G., Quinton, A., Mégraud, F., Lemaire, M., Quinten, A., De Mascarel, A., Webb, P., Forman, D., Knight, T., Wilson, A., Graves, S., Newell, D., Elder, J., Tonelli, E., Gatte, M. R. A., Ghironzi, G. C., Giulianelli, G., Bamford, K. B., Collins, J. S. A., Bickley, J., Johnston, B. T., Potts, S., Boston, V., Owen, R. J., Sloan, J., Basso, L., Lawlor, S., Clune, J., Szelényi, H., Stohmeyer, G., Macedo, G., Iglésias, I., Chaves, A. P., Loureiro, A., Katelaris, P. H., Seow, F., Lin, B., Napoli, J., Hones, D. B., Ngu, M. C., Akopyantz, Natalia S., Bukanov, Nikolay O., Westblom, T. Ulf, Berg, Douglas E., Nyst, J. F., Denis, P., Buset, M., De Reuck, M., Nielsen, H., Andersen, L. P., Birkholz, Sabine, Knipp, Ulrich, Nietzki, Claudia, Opferkuch, Wolfgang, Crabtree, J. E., Peichl, P., Lindly, I. J. D., Deusch, K., Seifirth, C., Funk, A., Dahie, I., Reut, K., Classen, M., Gionchetti, P., Vaira, D., Campieri, M., Bertinelli, E., Menegatti, M., Belluzzi, A., Briognola, C., Miglioli, M., Barbara, L., Tommaso, A. Di, Magistris, M. T. De, Bugnoli, M., Petracca, R., Covacci, A., Censini, S., Rappuoli, R., Abrignani, S., Territo, M. C., Smela, K. L., Reeve, J. R., Lee, T. D., Walsh, J. H., Armellini, D., Crabtree, J. E., Xiang, Z. Y., Mitchell, H. M., Hu, P. J., Li, Y. Y., Wang, Z. J., Zhao, S. M., Liu, Q., Chen, M., Du, G. G., Filipe, M. I., Reed, P. I., Craanen, M. E., Blok, P., Dekker, W., Colombo, E., Redaelli, D., Santangelo, M., Spinelli, M., Farinati, F., Valiante, F., Delia Libera, G., Germanà, B., Baffa, R., Rugge, M., Vianelo, F., Di Mario, F., Sipponen, Pentti, Rokkas, T., Popotheodorou, G., Kaldgeropoulos, N., Deprez, C., Galand, P., Fox, J. G., Wishnok, P., Murphy, J. C., Tannenbaum, S., Correa, P., Parsonnet, Julie, Macor, C., Da Broi, G. L., Avellinio, C., Reifen, R., Rasooly, I., Millson, M. E., Murphy, K., Thomas, J. E., Eastham, E. J., Malorgio, E., Dell’Olio, D., Kemmer, T. P., Dominguez-Munoz, J. E., Klingel, H., Gatto, M. R. A., Olivieri, R., Bayeli, R. F., Abate, L., De Gregorio, L., Aziz, J., Esposito, E., Basagni, C., Guilluy, R., Rousseau-Tsangaris, M., Brazier, J. L., Wadstiöm, Torkel, Tyszkiewicz, Tadeusz, Bergenzaun, Per, Olsson, Karin, Birac, C., Tall, F., Albenque, M., Labigne, A., Megraud, F., Feldman, R. A., Deeks, J., Glupczynski, Y., Burette, A., Goossens, H., Van den Boore, C., Butzler, J. P., Veldhuyzen van Zanten, S., Best, L., Benzanson, G., Haldane, D., Hazell, S., Mapstone, N. P., Lynch, D. A. F., Quirke, P., Taylor, D. E., Chang, N., Eaton, M., Stockdale, E., Salama, S. M., Thompson, L., Cockayne, A., Spiller, R. C., Leen, E., Sweeney, E., Klann, H., Hatz, R., Bornschein, W., Simon, T., Eimiller, A., Bolle, F., Schweikert, C., Köpeke, W., Moss, S. F., Bishop, A. E., Calam, J., Cahill, R. J., Xia, H., Solnick, J., and Tompkins, L.

Published
1992
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7. Azide inhibits human cytochrome P -4502E1, 1A2, and 3A4.

Author

Salmela KS, Tsyrlov IB, and Lieber CS

Subjects
Binding, Competitive, Cytochrome P-450 CYP1A2 metabolism, Cytochrome P-450 CYP2E1 metabolism, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System metabolism, Ethanol metabolism, Humans, Microsomes, Liver enzymology, Mixed Function Oxygenases metabolism, Oxidation-Reduction, Recombinant Proteins antagonists & inhibitors, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP2E1 Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors pharmacology, Mixed Function Oxygenases antagonists & inhibitors, Sodium Azide pharmacology
Abstract

Background: Recently, we showed that, in addition to cytochrome P-4502E1 (CYP2E1), CYP1A2 and CYP3A4 also contribute to the microsomal ethanol oxidizing system (MEOS). When MEOS activity is measured, sodium azide commonly is used to block the contaminating catalase. However, although CYP2E1 is considered insensitive to azide, its effect on the other P-450s is unknown. Therefore, the aim of the present study was to determine the effect of azide on human recombinant and hepatic CYP2E1, CYP1A2, and CYP3A4., Methods and Results: Concentrations of sodium azide as low as 0.1 mM markedly inhibited the specific ethanol oxidation (mean +/- SEM) by recombinant CYP1A2 and CYP3A4 expressed in HepG2 cells (to 16 +/- 1% and 22 +/- 2% of control without azide, respectively; p < 0.01). By contrast, the specific activity of CYP2E1 was only slightly (and not significantly) inhibited at this azide concentration (to 79 +/- 12% of control). Similarly, in human liver microsomes (n = 6), 0.1 mM azide strongly inhibited CYP1A2-dependent (to 25 +/- 2%) and CYP3A4-dependent (to 15 +/- 2%) ethanol oxidation, whereas CYP2E1 was inhibited only at 10 mM azide (to 60 +/- 10%). Azide also strongly affected the apparent kinetic values of all three isoenzymes. Furthermore, azide inhibited the specific monooxygenase activities, both by recombinant and microsomal P-450s. CYP2E1-specific p-nitrophenol hydroxylation was the most sensitive to azide, whereas CYP1A2-dependent 7-methoxyresorufin O-dealkylation was only slightly inhibited. Judging from its effect on p-nitrophenol hydroxylation by human liver microsomes, the inhibition of azide was competitive (Ki 0.09 mM)., Conclusions: Sodium azide at a concentration as low as 0.1 mM inhibited ethanol oxidation by CYP1A2 and CYP3A4. With CYP2E1, although oxidation of 50 mM ethanol was not inhibited by 0.1 mM azide, higher azide concentrations were inhibitory and 0.1 mM azide seemed to affect the kinetics of ethanol oxidation by CYP2E1. Therefore, azide should be avoided when measuring the MEOS activity because it may lead to underestimation, especially of CYP1A2- and CYP3A4-dependent ethanol oxidation.

Published
2001

8. Respective roles of human cytochrome P-4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system.

Author

Salmela KS, Kessova IG, Tsyrlov IB, and Lieber CS

Subjects
Adolescent, Adult, Cell Line, Child, Child, Preschool, Cytochrome P-450 CYP3A, Female, Humans, Liver Diseases, Alcoholic enzymology, Male, Cytochrome P-450 CYP1A2 physiology, Cytochrome P-450 CYP2E1 physiology, Cytochrome P-450 Enzyme System physiology, Ethanol pharmacokinetics, Microsomes, Liver enzymology, Mixed Function Oxygenases physiology
Abstract

The microsomal ethanol oxidizing system comprises an ethanol-inducible cytochrome P-4502E1, but the involvement of other P-450s has also been suggested. In our study, human CYP2E1, CYP1A2, and CYP3A4 were heterologously expressed in HepG2 cells, and their ethanol oxidation was assessed using a corresponding selective inhibitor: all three P-450 isoenzymes metabolized ethanol. Selective inhibitors-4-methylpyrazole (CYP2E1), furafylline (CYP1A2), and troleandomycin (CYP3A4)-also decreased microsomal ethanol oxidation in the livers of 18 organ donors. The P-450-dependent ethanol oxidizing activities correlated significantly with those of the specific monooxygenases and the immunochemically determined microsomal content of the respective P-450. The mean CYP2E1-dependent ethanol oxidation in human liver microsomes [1.41+/-0.11 nmol min(-1) (mg protein)(-1)] was twice that of CYP1A2 (0.61+/-0.07) or CYP3A4 (0.73+/-0.11) (p < 0.05). Furthermore, CYP2E1 had the highest (p < 0.05) specific activity [28+/-2 nmol min(-1) (nmol CYP2E1)(-1) versus 17+/-3 nmol min(-1) (nmol CYP1A2)(-1), and 12+/-2 nmol min(-1) (CYP3A4)(-1), respectively]. Thus, in human liver microsomes, CYP2E1 plays the major role. However, CYP1A2 and CYP3A4 contribute significantly to microsomal ethanol oxidation and may, therefore, also be involved in the pathogenesis of alcoholic liver disease.

Published
1998

9. Microsomal acetaldehyde oxidation is negligible in the presence of ethanol.

Author

Wu YS, Salmela KS, and Lieber CS

Subjects
Animals, Male, Oxidation-Reduction, Rats, Rats, Sprague-Dawley, Acetaldehyde pharmacokinetics, Alcohol Oxidoreductases physiology, Cytochrome P-450 Enzyme System physiology, Ethanol pharmacokinetics, Microsomes, Liver enzymology
Abstract

The microsomal ethanol oxidizing system (MEOS), inducible by ethanol and acetone, oxidizes ethanol to acetaldehyde, which causes many toxic effects associated with excess ethanol. Recent studies reported that rat liver microsomes also oxidize acetaldehyde, thereby challenging the validity of the assessment of MEOS activity by measuring acetaldehyde production and suggesting that MEOS activity results in the accumulation not of acetaldehyde but, rather, of its less toxic metabolite, acetate. To address these issues, we compared both metabolic rates of ethanol and acetaldehyde and the effect of ethanol on the acetaldehyde metabolism. Liver microsomes were prepared from Sprague-Dawley rats induced either with acetone for 3 days or ethanol for 3 weeks. NADPH-dependent acetaldehyde (300 microM) metabolism was measured in two ways: (1) by detection of acetaldehyde disappearance by headspace gas chromatography, and (2) by assessment of acetaldehyde oxidation by liquid scintillation counting of acetate formed from [1,2-14C]acetaldehyde. Ethanol (50 mM) oxidation was measured by gas chromatography. In acetone- and ethanol-induced rat liver microsomes, the acetaldehyde disappearance (p < 0.0001) and oxidation (p < 0.0001) rates were both significantly increased. The rates of acetaldehyde oxidation paralleled those of p-nitrophenol hydroxylation (r = 0.974, p < 0.0001), with a Km of 82+/-14 microM and a Vmax of 4.8+/-0.5 nmol/min/mg protein in acetone-induced microsomes. Acetaldehyde disappearance in acetone-induced microsomes and acetaldehyde oxidation in acetone-induced and ethanol-induced microsomes were significantly lower than the corresponding ethanol oxidation, with rates (nmol/min/mg protein) of 4.6+/-0.6 versus 9.0+/-0.8 (p < 0.005), 4.4+/-0.3 versus 9.1+/-0.5 (p < 0.0005), and 14.0+/-0.9 versus 19.5+/-1.8 (p < 0.05), respectively. The presence of 50 mM ethanol decreased this metabolism to 0.9+/-0.3 (p < 0.005), 0.5+/-0.1 (p < 0.001), and 1.8+/-0.3 (p < 0.001), resulting in rates of acetaldehyde metabolism of only 9.8+/-3.2%, 6.0+/-0.5%, and 9.5+/-1.2% (respectively) of those of ethanol oxidation. In conclusion, rat liver microsomes oxidize acetaldehyde at much lower rates than ethanol, and this acetaldehyde metabolism is strikingly inhibited by ethanol. Accordingly, acetaldehyde formation provides an accurate assessment of MEOS activity. Furthermore, because acetaldehyde production vastly exceeds its oxidation, the net result of MEOS activity is the accumulation of this toxic metabolite.

Published
1998

10. Binding of acetaldehyde to rat gastric mucosa during ethanol oxidation.

Author

Salmela KS, Sillanaukee P, Itälä L, Väkeväinen S, Salaspuro M, and Roine RP

Subjects
Acetates metabolism, Alcohol Dehydrogenase antagonists & inhibitors, Animals, Azides pharmacology, Carbon Radioisotopes, Fomepizole, Gastric Mucosa drug effects, Kinetics, Male, Protein Binding, Pyrazoles pharmacology, Radioisotope Dilution Technique, Rats, Rats, Wistar, Sodium Azide, Acetaldehyde metabolism, Ethanol metabolism, Gastric Mucosa metabolism, Proteins metabolism
Abstract

Acetaldehyde, the first product of ethanol metabolism, has previously been shown to form potentially harmful adducts with various proteins. The aim of this study was to investigate whether acetaldehyde--either exogenous or metabolically derived--binds to gastric mucosal proteins. Homogenized rat gastric mucosa was incubated with various concentrations of radiolabeled acetaldehyde or ethanol for different time periods. Acetaldehyde-protein adducts were determined by a liquid scintillation counter. In addition, mucosa was incubated with nonlabeled ethanol, and the acetaldehyde formed was measured by using headspace gas chromatography. Incubation of gastric mucosa with (14C)-acetaldehyde led to a concentration- and time-dependent radiolabeling of mucosal proteins. Formation of acetaldehyde adducts occurred relatively rapidly within 30 minutes and even at low acetaldehyde levels (5 micromol/L). Stable adducts represented 77% +/- 5% (mean +/- SEM) of the total adducts formed. In the presence of ethanol, acetaldehyde production and adduct formation took place in a concentration- and time-dependent manner. 4-Methylpyrazole and sodium azide inhibited acetaldehyde production to 7% +/- 1% of control and decreased the amount of acetaldehyde adducts to 55% +/- 8%. Enhanced acetaldehyde formation (to 420% +/- 50%) was clearly reflected in increased adduct formation (550% +/- 110%). In conclusion, both exogenous and endogenous acetaldehyde binds to gastric mucosal proteins in vitro. Gastric mucosal acetaldehyde production and the consequent adduct formation could be a pathogenetic factor behind ethanol-associated gastric injury.

Published
1997
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11. Role of catalase in rat gastric mucosal ethanol metabolism in vitro.

Author

Salmela KS, Kaihovaara P, Salaspuro M, and Roine RP

Subjects
Acetaldehyde metabolism, Alcohol Dehydrogenase physiology, Animals, Culture Techniques, Hydrogen-Ion Concentration, Male, Rats, Rats, Wistar, Catalase physiology, Ethanol pharmacokinetics, Gastric Mucosa enzymology
Abstract

To evaluate the possible role of catalase in gastric ethanol metabolism in rats, we studied acetaldehyde formation from ethanol by gastric mucosal homogenate under various in vitro conditions. Homogenized rat gastric mucosa produced significant amounts of acetaldehyde in a time and ethanol concentration-dependent manner, even in the absence of added NAD. Both acetaldehyde formation and catalase activity peaked around the physiological pH, whereas alcohol dehydrogenase (ADH) activity was in that pH range low and reached peak values only at a higher pH of 9 to 10. Catalase inhibitors sodium azide (SA) and 3-amino-1,2,4-triazole (3-AT) had little effect on ADH activity but markedly decreased catalase activity and acetaldehyde formation (1 mM of SA to 56 +/- 13% of control, 5 mM of 3-AT to 67 +/- 3% of control; mean +/- SE). 4-Methylpyrazole decreased ADH activity significantly, but did not affect acetaldehyde formation. Heating of the homogenate at 60 degrees C for 5 min decreased ADH activity only slightly, but totally abolished catalase activity and reduced acetaldehyde formation to 39 +/- 3% of control. Addition of a H2O2 generating system (beta-D(+)-glucose + glucose oxidase] increased acetaldehyde formation in a concentration-dependent manner up to 8-fold of the control value. Our results strongly suggest that, in addition to ADH, catalase may play a significant role in gastric ethanol metabolism in rats.

Published
1996
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12. Alcohol metabolism in Helicobacter pylori-infected stomach.

Author

Roine RP, Salmela KS, and Salaspuro M

Subjects
Acetaldehyde metabolism, Alcohol Dehydrogenase metabolism, Animals, Gastric Mucosa metabolism, Gastritis microbiology, Humans, Mice, Ethanol metabolism, Gastritis metabolism, Helicobacter Infections metabolism, Helicobacter pylori enzymology
Abstract

Studies in our laboratory have revealed that Helicobacter pylori exhibits significant cytosolic alcohol dehydrogenase activity and that the enzyme is fully active at ethanol concentrations prevailing in the stomach during alcohol consumption or after alcohol is completely absorbed from the stomach and is available through blood circulation only. Moreover, even the low levels of endogenous ethanol found in the stomach can be oxidized to acetaldehyde by H. pylori alcohol dehydrogenase. The metabolic significance of the enzyme remains as yet unresolved. Under microaerobic conditions, however, the enzyme could be of importance in the energy metabolism of the organism. In the presence of excess ethanol, H. pylori alcohol dehydrogenase produces significant amounts of acetaldehyde. Acetaldehyde is a toxic and reactive compound and could theoretically be a pathogenetic factor in H. pylori-associated gastric injury. Preliminary studies have indicated that acetaldehyde inhibits gastric mucosal regeneration and forms stable adducts with mucosal proteins. Both of these mechanisms could cause gastric injury. The role of H. pylori-related acetaldehyde formation in vivo, however, needs to be established in future studies. In antral human gastric mucosa, H. pylori infection is associated with a significant decrease in alcohol dehydrogenase activity. Similarly, in specific pathogen-free mice with a prolonged infection, gastric alcohol dehydrogenase activity is decreased; however, this is not clearly reflected in the bioavailability of ethanol or the amount of its first pass metabolism.

Published
1995
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13. Helicobacter infection and gastric ethanol metabolism.

Author

Salmela KS, Salaspuro M, Gentry RT, Methuen T, Höök-Nikanne J, Kosunen TU, and Roine RP

Subjects
Acetaldehyde metabolism, Adult, Alcohol Dehydrogenase physiology, Animals, Bacteriological Techniques, Biopsy, Female, Gastric Mucosa microbiology, Gastric Mucosa pathology, Gastritis microbiology, Gastritis pathology, Helicobacter enzymology, Helicobacter Infections microbiology, Helicobacter Infections pathology, Humans, Male, Metabolic Clearance Rate physiology, Mice, Mice, Inbred BALB C, Middle Aged, Ethanol pharmacokinetics, Gastric Mucosa enzymology, Gastritis enzymology, Helicobacter Infections enzymology, Helicobacter pylori enzymology
Abstract

The organism frequently colonizing the stomach of patients suffering from chronic active gastritis and peptic ulcer disease--Helicobacter pylori--possesses marked alcohol dehydrogenase (ADH) activity. Consequently, Helicobacter infection may contribute to the capacity of the stomach to metabolize ethanol and lead to increased acetaldehyde production. To study this hypothesis, we first determined ADH activity in a variety of H. pylori strains originally isolated from human gastric mucosal biopsies. ADH activity was also measured in endoscopic gastric mucosal specimens obtained from H. pylori-positive and -negative patients. Furthermore, we used a mouse model of Helicobacter infection to determine whether infected animals exhibit more gastric ethanol metabolism than noninfected controls. Most of the 32 H. pylori strains studied possessed clear ADH activity and produced acetaldehyde. In humans, gastric ADH activity of corpus mucosa did not differ between H. pylori-positive and -negative subjects, whereas in antral biopsies ADH activity was significantly lower in infected patients. In mice, gastric ADH activity was similar or even lower in infected animals than in controls, depending on the duration of infection, despite the fact that the infectious agent used--Helicobacter felis--showed ADH activity in vitro. In accordance with this, Helicobacter infection tended to decrease rather than increase gastric ethanol metabolism in mice. In humans, it remains to be established whether the observed decrease in antral ADH activity associated with H. pylori infection can lead to reduced gastric first-pass metabolism of ethanol.

Published
1994
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14. Purification and characterization of Helicobacter pylori alcohol dehydrogenase.

Author

Kaihovaara P, Salmela KS, Roine RP, Kosunen TU, and Salaspuro M

Subjects
Acetaldehyde metabolism, Chromatography, Affinity, Chromatography, Ion Exchange, Electrophoresis, Polyacrylamide Gel, Ethanol pharmacokinetics, Humans, Hydrogen-Ion Concentration, Oxidation-Reduction, Alcohol Dehydrogenase isolation & purification, Helicobacter pylori enzymology
Abstract

Alcohol dehydrogenase of Helicobacter pylori (HPADH) was purified from the soluble fraction of cultured bacteria (strain NCTC 11637) by anion exchange and affinity chromatography. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the 160-fold purified enzyme displayed one protein band with a mobility that corresponded to an M(r) of 38,000. Although HPADH was capable of utilizing both NADP and NAD as cofactors in alcohol oxidation, it showed a strong preference for NADP over NAD. Kinetic studies revealed a Km value of 26 mM and a kcat value of 530 min-1 for ethanol/active site at 37 degrees C in 0.1 M potassium phosphate buffer (pH 7.4). The enzyme was considerably more active toward primary aliphatic alcohols than secondary alcohols. The Km and kcat values decreased as the chain length of the alcohol increased. Benzyl alcohol was a 100 times better substrate than ethanol in terms of kcat/Km values. At neutral pH, HPADH was more effective in aldehyde reduction than in alcohol oxidation. Because of its high specific activity for ethanol (14 units mg-1) under physiological conditions, HPADH can also effectively produce acetaldehyde at higher ethanol levels. This reversed function of HPADH and the production of toxic and reactive acetaldehyde could account for at least some of the gastrointestinal morbidity associated with H. pylori infection.

Published
1994
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15. Carbohydrate-deficient transferrin during 3 weeks' heavy alcohol consumption.

Author

Salmela KS, Laitinen K, Nyström M, and Salaspuro M

Subjects
Adult, Alcohol Drinking adverse effects, Alcoholism rehabilitation, Biomarkers blood, Humans, Liver Function Tests, Male, Middle Aged, Transferrin metabolism, Alcohol Drinking blood, Alcoholism blood, Transferrin analogs & derivatives
Abstract

To study the effect of controlled heavy drinking of 60 g ethanol/day for 3 weeks on carbohydrate-deficient transferrin (CDT), a commercial double antibody kit (CDTect) was used. By the end of the third drinking week, a statistically significant increase in the mean CDT level was observed. When compared to AST and gamma-glutamyltransferase, CDT was a more informative marker. However, only in 2 of the 10 volunteers did CDT exceed the upper normal level (20 units/liter) recommended by the manufacturer. This indicates that the sensitivity of CDT to detect heavy drinking is lower than that previously reported. The higher accuracy has in general been obtained in studies comparing healthy controls with a low alcohol consumption to alcoholics with an alcohol consumption higher than that used in the present experiment. Our results suggest that it remains to be established whether CDT, although better than AST and gamma-glutamyltransferase, will provide a clinically useful tool in identifying heavy drinkers in populations covering a wide range of alcohol consumption.

Published
1994
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16. Characteristics of Helicobacter pylori alcohol dehydrogenase.

Author

Salmela KS, Roine RP, Koivisto T, Höök-Nikanne J, Kosunen TU, and Salaspuro M

Subjects
Acetaldehyde metabolism, Aldehyde Dehydrogenase metabolism, Cell Division drug effects, Fomepizole, Helicobacter pylori growth & development, Isoelectric Focusing, Pyrazoles pharmacology, Staining and Labeling, Alcohol Dehydrogenase metabolism, Helicobacter pylori enzymology
Abstract

Background: Helicobacter pylori shows alcohol dehydrogenase activity, which in the presence of ethanol leads to in vitro production of acetaldehyde, a toxic and highly reactive substance. The present study was undertaken to further define H. pylori-related ethanol and acetaldehyde metabolism by characterizing H. pylori alcohol dehydrogenase and by determining whether the organism possesses aldehyde dehydrogenase., Methods: Cytosolic alcohol and aldehyde dehydrogenase activities were determined spectrophotometrically. Acetaldehyde produced by cytosol during incubation with ethanol was measured by head space gas chromatography. Isoenzyme pattern was studied using isoelectric focusing., Results: Significant alcohol dehydrogenase activity was observed at a neutral pH known to occur in gastric mucus. The Km for ethanol oxidation was approximately 100 mmol/L for the two strains tested. Acetaldehyde was formed already from a low ethanol concentration known to prevail in the stomach endogenously. Isoelectric focusing of the enzyme showed activity bands with pI at 7.1-7.3, a pattern different from that of gastric mucosal alcohol dehydrogenase. 4-methylpyrazole inhibited enzyme activity in a competitive manner and suppressed the growth of the organism during culture. Neither Helicobacter strain studied showed aldehyde dehydrogenase activity and can thus not remove acetaldehyde by that pathway., Conclusions: Acetaldehyde production by H. pylori from exogenous or endogenous ethanol may be a pathogenetic mechanism behind mucosal injury associated with the organism.

Published
1993
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17. Blood dolichol in lysosomal diseases.

Author

Jokelainen K, Salmela KS, Humaloja K, Roine R, Autio S, Arvio M, Järvelä I, Nykänen I, Palo J, and Salaspuro M

Subjects
Adolescent, Adult, Aspartylglucosaminuria, Child, Child, Preschool, Esters blood, Female, Humans, Male, Middle Aged, Neuronal Ceroid-Lipofuscinoses blood, Dolichols blood, Lysosomal Storage Diseases blood
Abstract

Highly elevated serum total dolichol (free dolichol + dolichyl ester) concentrations have recently been found in two lysosomal storage diseases, aspartylglucosaminuria (AGU) and mannosidosis. The present study demonstrates that the increase of serum dolichol in AGU patients is caused by an increase of serum free dolichol. In 15 patients the mean serum level of free dolichol (227 +/- 16 ng/mL) was 1.9 times higher (p < 0.001) than that in healthy controls (120 +/- 6 ng/mL), while the amounts of dolichol fatty acid esters were similar in the patients and controls (110 +/- 9 vs. 118 +/- 6 ng/mL). In contrast, 10 patients with neuronal ceroid-lipofuscinosis (NCL) (three with infantile, four with juvenile, and three with variant late infantile NCL) had significantly (p < 0.01) lower mean serum levels of both free (79 +/- 5 ng/mL) and total (159 +/- 6 ng/mL) dolichol than age-adjusted healthy controls (free, 100 +/- 6 ng/mL; total, 206 +/- 14 ng/mL). Decreased blood dolichol has not been reported earlier for any other disease. We conclude that the increased serum free dolichol in AGU reflects disturbed lysosomal function and that the decreased free and esterified dolichols in NCLs speak against their presumed primary lysosomal nature.

Published
1992
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18. Alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori--a possible mechanism behind gastric injury.

Author

Roine RP, Salmela KS, Höök-Nikanne J, Kosunen TU, and Salaspuro M

Subjects
Cytosol metabolism, Gram-Negative Bacteria metabolism, Helicobacter pylori enzymology, Acetaldehyde metabolism, Alcohol Dehydrogenase metabolism, Gastric Mucosa microbiology, Helicobacter pylori metabolism
Abstract

Two standard Helicobacter pylori strains showed significant cytosolic alcohol dehydrogenase activity and produced considerable amounts of acetaldehyde when incubated with an ethanol containing solution in vitro. The alcohol dehydrogenase activity of the Helicobacter pylori strains was almost as high as that found in Klebsiella pneumoniae and far greater than that in Escherichia coli or Campylobacter jejuni. The amount of acetaldehyde produced by cytosol prepared from Helicobacter pylori exceeded that by any of the other bacteria studied. The bacterial production of acetaldehyde--a highly toxic and reactive substance--could be an important factor in the pathogenesis of Helicobacter pylori associated gastric injury and increased risk of gastric cancer.

Published
1992
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19. Colloidal bismuth subcitrate and omeprazole inhibit alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori.

Author

Roine RP, Salmela KS, Höök-Nikanne J, Kosunen TU, and Salaspuro M

Subjects
Bismuth pharmacology, Helicobacter pylori enzymology, Helicobacter pylori metabolism, Acetaldehyde metabolism, Alcohol Dehydrogenase antagonists & inhibitors, Anti-Ulcer Agents pharmacology, Helicobacter pylori drug effects, Omeprazole pharmacology, Organometallic Compounds pharmacology
Abstract

We have recently shown that Helicobacter pylori possesses marked alcohol dehydrogenase (ADH) activity and is capable--when incubated with an ethanol containing solution in vitro--of producing large amounts of acetaldehyde. In the present study we report that some drugs commonly used for the eradication of H. pylori and for the treatment of gastroduodenal diseases are potent ADH inhibitors and, consequently, effectively prevent bacterial oxidation of ethanol to acetaldehyde. Colloidal bismuth subcitrate (CBS), already at a concentration of 0.01 mM, inhibited H. pylori ADH by 93% at 0.5 M ethanol and decreased oxidation of 22 mM ethanol to acetaldehyde to 82% of control. At concentrations above 5 mM, CBS almost totally inhibited acetaldehyde formation. Omeprazole, a drug also known to suppress growth of H. pylori, also inhibited H. pylori ADH and suppressed bacterial acetaldehyde formation significantly to 69% of control at a drug concentration of 0.1 mM. By contrast, the H2-receptor antagonists ranitidine and famotidine showed only modest effect on bacterial ADH and acetaldehyde production. We suggest that inhibition of bacterial ADH and a consequent suppression of acetaldehyde production from endogenous or exogenous ethanol may be a novel mechanism by which CBS and omeprazole exert their effect both on the growth of H. pylori as well as on H. pylori associated gastric injury.

Published
1992
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