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Free radical scavengers and inflammatory bowel disease
872
CORRESPONDENCE
hepatitis C virus, the principal non-A, non-B hepatitis (8).
GASTROENTEROLOGY
etiologic
agent
of (nonenteric)
GARYP.WORMSER,M.D. Division of Infectious Diseases Department of Medicine New York Medical College Valhalla, New York 10595 1. Seeff LB, Wright
EC, Zimmerman HJ, Alter HJ, Dietz AA, Felsher BF, Finkelstein JD, Garcia-Pont P, Gerin JL, Greenlee HB, Hamilton J, Holland PV, Kaplan PM, Kiernan T, Koff RS, Leevy CM, McAuliffe VJ, Nath N, Purcell RH, Schiff ER, Schwartz CC, Tamburro CH, Vlahcevic Z, Zemel R, Zimmon DS. Type B hepatitis after needle-stick exposure: Prevention with hepatitis B immune globulin. Final report of the Veterans Administration Cooperative Study. Ann Intern Med 1978;88:285-293. 2. Beekmann SE, Fahey BJ, Gerberding JL, Henderson DK. Risky business: using necessarily imprecise casualty counts to estimate occupational risk for HIV-I infection. Infect Control Hosp Epidemiol1990;11:371-379. E, Taylor JW. Non-A, non-B hepatitis 3. Herron W, Peterson infection transmitted via a needle-stick-Washington. MMWR 1979;28:157-158. 4. Neefe JR, Norris RF, Reinhold JG, Mitchell CB, Howell DS. Carriers of hepatitis virus in the blood and viral hepatitis in whole blood recipients. 1. Studies on donors suspected as carriers of hepatitis virus and as sources of post-transfusion viral hepatitis. JAMA 1954;154:1066-1071. 5. Murray R, Diefenbach WCL, Ratner F, Leone NC, Oliphant JW. Hepatitis carrier state 2. Confirmation of carrier state by transmission experiments in volunteers. JAMA 1954;154:1072-1074. 6. Hoofnagle JH, Gerety RJ, Tabor E, Feinstone SM, Barker LF, Purcell RH. Transmission of non-A, non-B hepatitis. Ann Intern Med 1977;87:14-20. 7. Napoli VM, McGowan JE Jr. How much blood is in a needlestick? J Infect Dis 1987;155:828. 8. Kuo G, Choo Q-L, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee W-S, Kuo C, Berger K, Shuster JR, Oberby LR, Bradley DW, Houghton M. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-364.
Free Radical Scavengers Bowel Disease
and Inflammatory
The recent correspondence (1,2) concerning free radical scavenging and inflammatory bowel disease illustrates some fundamental misconceptions of the chemistry of free radicals. First, hydroxyl radicals are highly reactive tissue-damaging species that react with almost everything, and almost every drug in therapeutic use will act as an hydroxyl radical scavenger in vitro (3). Thus Kvietys and Grisham (2) are correct in their observation that both 4- and 5-aminosalicylates react with this radical at equal rates; all compounds with aromatic ring structures react very fast with hydroxyl radical (4). For reasons recently reviewed (3), hydroxyl radical scavenging is an unlikely mode of action in vivo for most drugs, simply because the drugs are never present in tissues at sufficiently high concentrations to compete with biological molecules for any hydroxyl radicals generated in vivo. What is often more important is the ability of a drug to prevent formation of hydroxyl radicals from hydrogen peroxide by binding the transition metal ions needed for this conversion (3,5); this may be an important feature of aminosalicylate action (2).
Vol. 101, No. 3
Second, another damaging species generated at sites of inflammation is hypochlorous acid, HOCl. Both 4- and 5-aminosalicylates are excellent scavengers of HOC1 (6,7), and they may also inhibit its formation by myeloperoxidase (2). The concentrations of aminosalicylates in the colon of patients being given these drugs (or sulfasalazine) are within the range at which HOC1 scavenging, and perhaps hydroxyl radical scavenging (6,8), could occur in vivo. Third, it must be realized that reaction of drugs with free radicals is not always a good thing because the resulting drug-derived radicals can sometimes themselves do biological damage (3). For example, we have recently proposed that many of the side effects of penicillamine in rheumatoid patients are caused by its reaction with oxygen-derived species, generating sulfur-containing radicals that can bind to proteins and generate antigenic determinants (9).
BARRYHALLWELL,PKD. Pulmonary Medicine University of California Davis Medical Center 4301XStreet Sacramento, California 95817 1. Allgayer H, Gugler R, Bohme P, Schmidt M, Hofer P, Kruis W. Is radical scavenging necessary in the treatment of inflammatory bowel disease? Gastroenterology 1991;100:581-582. 2. Kvietys PR, Grisham MB. Reply. Gastroenterology 1991;lOO:
582. 3. Halliwell
B. How to characterize a biological antioxidant. Free Radical Res Commun 1990;9:1-32. M, Gutteridge JMC. Methods for the 4. Halliwell B, Grootoveld measurement of hydroxyl radicals in biochemical systems. Deoxyribose degradation and aromatic hydroxylation. Methods Biochem Anal 1988;33:59-90. 5. Aruoma 01, Halliwell B. The iron binding and hydroxyl radical scavenging activity of anti-inflammatory drugs. Xenobiotica 1988;18:459-470. B, Hoey BM, Butler J. The 6. Aruoma 01, Wasil M, Halliwell scavenging of oxidants by sulfasalazine and its metabolites. A possible contribution to their anti-inflammatory effects? Biothem Pharmacol 1987;36:3739-3742. and inflammatory bowel 7. Halliwell B. Free radicals, antioxidants diseases. In: Peters TJ, ed. The cell biology of inflammation in the gastro-intestinal tract. Hull, England: Corners, 1990:29-49. I, Nielsen OH, Christensen A, Langholz E, Binder 8. Ahnfelt-Ronne V. Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid. Gastroenterology 1990;98:11621169. 9. Aruoma 01, Halliwell B, Butler J, Hoey BM. Apparent inactivation of a,-antiproteinase by sulphur-containing radicals derived from penicillamine. Biochem Pharmacol 1989;38:4353-4357.
Role of Parenteral Colitis
Nutrition
in Crohn’s
Dear Sir: In the article by Sitzmann et al. (l), the authors conclude that total parenteral nutrition and bowel rest along with aggressive medical therapy may induce long-term remission in patients with severe Crohn’s colitis resistant to medical therapy alone. However, there are many confounding variables in this retrospective study, which does not provide an independent assessment of total parentera1 nutrition; thus a major credit to total parenteral nutrition is probably not justified. One can only speculate on how many of these patients would have responded to aggressive medical therapy alone. Azathioprine therapy was started in 7 of 16 patients during hospitalization, and only 1 of these patients needed surgery. In contrast, only 2 of 22 patients with ulcerative colitis received
CORRESPONDENCE
hepatitis C virus, the principal non-A, non-B hepatitis (8).
GASTROENTEROLOGY
etiologic
agent
of (nonenteric)
GARYP.WORMSER,M.D. Division of Infectious Diseases Department of Medicine New York Medical College Valhalla, New York 10595 1. Seeff LB, Wright
EC, Zimmerman HJ, Alter HJ, Dietz AA, Felsher BF, Finkelstein JD, Garcia-Pont P, Gerin JL, Greenlee HB, Hamilton J, Holland PV, Kaplan PM, Kiernan T, Koff RS, Leevy CM, McAuliffe VJ, Nath N, Purcell RH, Schiff ER, Schwartz CC, Tamburro CH, Vlahcevic Z, Zemel R, Zimmon DS. Type B hepatitis after needle-stick exposure: Prevention with hepatitis B immune globulin. Final report of the Veterans Administration Cooperative Study. Ann Intern Med 1978;88:285-293. 2. Beekmann SE, Fahey BJ, Gerberding JL, Henderson DK. Risky business: using necessarily imprecise casualty counts to estimate occupational risk for HIV-I infection. Infect Control Hosp Epidemiol1990;11:371-379. E, Taylor JW. Non-A, non-B hepatitis 3. Herron W, Peterson infection transmitted via a needle-stick-Washington. MMWR 1979;28:157-158. 4. Neefe JR, Norris RF, Reinhold JG, Mitchell CB, Howell DS. Carriers of hepatitis virus in the blood and viral hepatitis in whole blood recipients. 1. Studies on donors suspected as carriers of hepatitis virus and as sources of post-transfusion viral hepatitis. JAMA 1954;154:1066-1071. 5. Murray R, Diefenbach WCL, Ratner F, Leone NC, Oliphant JW. Hepatitis carrier state 2. Confirmation of carrier state by transmission experiments in volunteers. JAMA 1954;154:1072-1074. 6. Hoofnagle JH, Gerety RJ, Tabor E, Feinstone SM, Barker LF, Purcell RH. Transmission of non-A, non-B hepatitis. Ann Intern Med 1977;87:14-20. 7. Napoli VM, McGowan JE Jr. How much blood is in a needlestick? J Infect Dis 1987;155:828. 8. Kuo G, Choo Q-L, Alter HJ, Gitnick GL, Redeker AG, Purcell RH, Miyamura T, Dienstag JL, Alter MJ, Stevens CE, Tegtmeier GE, Bonino F, Colombo M, Lee W-S, Kuo C, Berger K, Shuster JR, Oberby LR, Bradley DW, Houghton M. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 1989;244:362-364.
Free Radical Scavengers Bowel Disease
and Inflammatory
The recent correspondence (1,2) concerning free radical scavenging and inflammatory bowel disease illustrates some fundamental misconceptions of the chemistry of free radicals. First, hydroxyl radicals are highly reactive tissue-damaging species that react with almost everything, and almost every drug in therapeutic use will act as an hydroxyl radical scavenger in vitro (3). Thus Kvietys and Grisham (2) are correct in their observation that both 4- and 5-aminosalicylates react with this radical at equal rates; all compounds with aromatic ring structures react very fast with hydroxyl radical (4). For reasons recently reviewed (3), hydroxyl radical scavenging is an unlikely mode of action in vivo for most drugs, simply because the drugs are never present in tissues at sufficiently high concentrations to compete with biological molecules for any hydroxyl radicals generated in vivo. What is often more important is the ability of a drug to prevent formation of hydroxyl radicals from hydrogen peroxide by binding the transition metal ions needed for this conversion (3,5); this may be an important feature of aminosalicylate action (2).
Vol. 101, No. 3
Second, another damaging species generated at sites of inflammation is hypochlorous acid, HOCl. Both 4- and 5-aminosalicylates are excellent scavengers of HOC1 (6,7), and they may also inhibit its formation by myeloperoxidase (2). The concentrations of aminosalicylates in the colon of patients being given these drugs (or sulfasalazine) are within the range at which HOC1 scavenging, and perhaps hydroxyl radical scavenging (6,8), could occur in vivo. Third, it must be realized that reaction of drugs with free radicals is not always a good thing because the resulting drug-derived radicals can sometimes themselves do biological damage (3). For example, we have recently proposed that many of the side effects of penicillamine in rheumatoid patients are caused by its reaction with oxygen-derived species, generating sulfur-containing radicals that can bind to proteins and generate antigenic determinants (9).
BARRYHALLWELL,PKD. Pulmonary Medicine University of California Davis Medical Center 4301XStreet Sacramento, California 95817 1. Allgayer H, Gugler R, Bohme P, Schmidt M, Hofer P, Kruis W. Is radical scavenging necessary in the treatment of inflammatory bowel disease? Gastroenterology 1991;100:581-582. 2. Kvietys PR, Grisham MB. Reply. Gastroenterology 1991;lOO:
582. 3. Halliwell
B. How to characterize a biological antioxidant. Free Radical Res Commun 1990;9:1-32. M, Gutteridge JMC. Methods for the 4. Halliwell B, Grootoveld measurement of hydroxyl radicals in biochemical systems. Deoxyribose degradation and aromatic hydroxylation. Methods Biochem Anal 1988;33:59-90. 5. Aruoma 01, Halliwell B. The iron binding and hydroxyl radical scavenging activity of anti-inflammatory drugs. Xenobiotica 1988;18:459-470. B, Hoey BM, Butler J. The 6. Aruoma 01, Wasil M, Halliwell scavenging of oxidants by sulfasalazine and its metabolites. A possible contribution to their anti-inflammatory effects? Biothem Pharmacol 1987;36:3739-3742. and inflammatory bowel 7. Halliwell B. Free radicals, antioxidants diseases. In: Peters TJ, ed. The cell biology of inflammation in the gastro-intestinal tract. Hull, England: Corners, 1990:29-49. I, Nielsen OH, Christensen A, Langholz E, Binder 8. Ahnfelt-Ronne V. Clinical evidence supporting the radical scavenger mechanism of 5-aminosalicylic acid. Gastroenterology 1990;98:11621169. 9. Aruoma 01, Halliwell B, Butler J, Hoey BM. Apparent inactivation of a,-antiproteinase by sulphur-containing radicals derived from penicillamine. Biochem Pharmacol 1989;38:4353-4357.
Role of Parenteral Colitis
Nutrition
in Crohn’s
Dear Sir: In the article by Sitzmann et al. (l), the authors conclude that total parenteral nutrition and bowel rest along with aggressive medical therapy may induce long-term remission in patients with severe Crohn’s colitis resistant to medical therapy alone. However, there are many confounding variables in this retrospective study, which does not provide an independent assessment of total parentera1 nutrition; thus a major credit to total parenteral nutrition is probably not justified. One can only speculate on how many of these patients would have responded to aggressive medical therapy alone. Azathioprine therapy was started in 7 of 16 patients during hospitalization, and only 1 of these patients needed surgery. In contrast, only 2 of 22 patients with ulcerative colitis received