Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1983 Jan 15;210(1):107–113. doi: 10.1042/bj2100107

Inhibition of microsomal oxidation of alcohols and of hydroxyl-radical-scavenging agents by the iron-chelating agent desferrioxamine.

A I Cederbaum, E Dicker
PMCID: PMC1154195  PMID: 6303308

Abstract

Rat liver microsomes (microsomal fractions) catalyse the oxidation of straight-chain aliphatic alcohols and of hydroxyl-radical-scavenging agents during NADPH-dependent electron transfer. The iron-chelating agent desferrioxamine, which blocks the generation of hydroxyl radicals in other systems, was found to inhibit the following microsomal reactions: production of formaldehyde from either dimethyl sulphoxide or 2-methylpropan-2-ol (t-butylalcohol); generation of ethylene from 4-oxothiomethylbutyric acid; release of 14CO2 from [I-14C]benzoate; production of acetaldehyde from ethanol or butanal (butyraldehyde) from butan-1-ol. Desferrioxamine also blocked the increase in the oxidation of all these substrates produced by the addition of iron-EDTA to the microsomes. Desferrioxamine had no effect on a typical mixed-function-oxidase activity, the N-demethylation of aminopyrine, nor on the peroxidatic activity of catalase/H2O2 with ethanol. H2O2 appears to be the precursor of the oxidizing radical responsible for the oxidation of the alcohols and the other hydroxyl-radical scavengers. Chelation of microsomal iron by desferrioxamine most likely decreases the generation of hydroxyl radicals, which results in an inhibition of the oxidation of the alcohols and the hydroxyl-radical scavengers. Whereas desferrioxamine inhibited the oxidation of 2-methylpropan-2-ol, dimethyl sulphoxide, 4-oxothiomethylbutyrate and benzoate by more than 90%, the oxidation of ethanol and butanol could not be decreased by more than 45-60%. Higher concentrations of desferrioxamine were required to block the metabolism of the primary alcohols than to inhibit the metabolism of the other substrates. The desferrioxamine-insensitive rate of oxidation of ethanol was not inhibited by competitive hydroxyl-radical scavengers. These results suggest that primary alcohols may be oxidized by two pathways in microsomes, one dependent on the interaction of the alcohols with hydroxyl radicals (desferrioxamine-sensitive), the other which appears to be independent of these radicals (desferrioxamine-insensitive).

Full text

PDF
107

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aust S. D., Roerig D. L., Pederson T. C. Evidence for superoxide generation by NADPH-cytochrome c reductase of rat liver microsomes. Biochem Biophys Res Commun. 1972 Jun 9;47(5):1133–1137. doi: 10.1016/0006-291x(72)90952-7. [DOI] [PubMed] [Google Scholar]
  2. Buettner G. R., Oberley L. W., Leuthauser S. W. The effect of iron on the distribution of superoxide and hydroxyl radicals as seen by spin trapping and on the superoxide dismutase assay. Photochem Photobiol. 1978 Oct-Nov;28(4-5):693–695. doi: 10.1111/j.1751-1097.1978.tb07001.x. [DOI] [PubMed] [Google Scholar]
  3. Cederbaum A. I., Cohen G. Oxidative demethylation of t-butyl alcohol by rat liver microsomes. Biochem Biophys Res Commun. 1980 Nov 28;97(2):730–736. doi: 10.1016/0006-291x(80)90325-3. [DOI] [PubMed] [Google Scholar]
  4. Cederbaum A. I., Dicker E., Cohen G. Effect of hydroxyl radical scavengers on microsomal oxidation of alcohols and on associated microsomal reactions. Biochemistry. 1978 Jul 25;17(15):3058–3064. doi: 10.1021/bi00608a018. [DOI] [PubMed] [Google Scholar]
  5. Cederbaum A. I., Dicker E., Cohen G. Role of hydroxyl radicals in the iron-ethylenediaminetetraacetic acid mediated stimulation of microsomal oxidation of ethanol. Biochemistry. 1980 Aug 5;19(16):3698–3704. doi: 10.1021/bi00557a010. [DOI] [PubMed] [Google Scholar]
  6. Cederbaum A. I., Dicker E., Rubin E., Cohen G. Effect of thiourea on microsomal oxidation of alcohols and associated microsomal functions. Biochemistry. 1979 Apr 3;18(7):1187–1191. doi: 10.1021/bi00574a011. [DOI] [PubMed] [Google Scholar]
  7. Cederbaum A. I., Qureshi A., Messenger P. Oxidation of isopropanol by rat liver microsomes: possible role of hydroxyl radicals. Biochem Pharmacol. 1981 Apr 15;30(8):825–831. doi: 10.1016/s0006-2952(81)80002-0. [DOI] [PubMed] [Google Scholar]
  8. Cohen G., Cederbaum A. I. Chemical evidence for production of hydroxyl radicals during microsomal electron transfer. Science. 1979 Apr 6;204(4388):66–68. doi: 10.1126/science.432627. [DOI] [PubMed] [Google Scholar]
  9. Cohen G., Cederbaum A. I. Microsomal metabolism of hydroxyl radical scavenging agents: relationship to the microsomal oxidation of alcohols. Arch Biochem Biophys. 1980 Feb;199(2):438–447. doi: 10.1016/0003-9861(80)90300-8. [DOI] [PubMed] [Google Scholar]
  10. Dybing E., Nelson S. D., Mitchell J. R., Sasame H. A., Gillette J. R. Oxidation of alpha-methyldopa and other catechols by cytochrome P-450-generated superoxide anion: possible mechanism of methyldopa hepatitis. Mol Pharmacol. 1976 Nov;12(6):911–920. [PubMed] [Google Scholar]
  11. Gutteridge J. M., Richmond R., Halliwell B. Inhibition of the iron-catalysed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine. Biochem J. 1979 Nov 15;184(2):469–472. doi: 10.1042/bj1840469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Halliwell B., Gutteridge J. M. Formation of thiobarbituric-acid-reactive substance from deoxyribose in the presence of iron salts: the role of superoxide and hydroxyl radicals. FEBS Lett. 1981 Jun 15;128(2):347–352. doi: 10.1016/0014-5793(81)80114-7. [DOI] [PubMed] [Google Scholar]
  13. Halliwell B. Superoxide-dependent formation of hydroxyl radicals in the presence of iron chelates: is it a mechanism for hydroxyl radical production in biochemical systems? FEBS Lett. 1978 Aug 15;92(2):321–326. doi: 10.1016/0014-5793(78)80779-0. [DOI] [PubMed] [Google Scholar]
  14. Halliwell B. Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. Its role in degradation of hyaluronic acid by a superoxide-generating system. FEBS Lett. 1978 Dec 15;96(2):238–242. doi: 10.1016/0014-5793(78)80409-8. [DOI] [PubMed] [Google Scholar]
  15. Heikkila R. E., Cabbat F. S. Inhibition of iron-stimulated catecholamine degradation by the iron-chelators DETAPAC and Desferal. Potentially useful laboratory agents. Biochem Pharmacol. 1981 Nov 1;30(21):2945–2947. doi: 10.1016/0006-2952(81)90257-4. [DOI] [PubMed] [Google Scholar]
  16. Klein S. M., Cohen G., Cederbaum A. I. Production of formaldehyde during metabolism of dimethyl sulfoxide by hydroxyl radical generating systems. Biochemistry. 1981 Oct 13;20(21):6006–6012. doi: 10.1021/bi00524a013. [DOI] [PubMed] [Google Scholar]
  17. Klein S. M., Cohen G., Cederbaum A. I. The interaction of hydroxyl radicals with dimethylsulfoxide produces formaldehyde. FEBS Lett. 1980 Jul 28;116(2):220–222. doi: 10.1016/0014-5793(80)80648-x. [DOI] [PubMed] [Google Scholar]
  18. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  19. Lieber C. S., DeCarli L. M. Hepatic microsomal ethanol-oxidizing system. In vitro characteristics and adaptive properties in vivo. J Biol Chem. 1970 May 25;245(10):2505–2512. [PubMed] [Google Scholar]
  20. Lieber C. S., DeCarli L. M. The role of the hepatic microsomal ethanol oxidizing system (MEOS) for ethanol metabolism in vivo. J Pharmacol Exp Ther. 1972 May;181(2):279–287. [PubMed] [Google Scholar]
  21. McCord J. M., Day E. D., Jr Superoxide-dependent production of hydroxyl radical catalyzed by iron-EDTA complex. FEBS Lett. 1978 Feb 1;86(1):139–142. doi: 10.1016/0014-5793(78)80116-1. [DOI] [PubMed] [Google Scholar]
  22. NASH T. The colorimetric estimation of formaldehyde by means of the Hantzsch reaction. Biochem J. 1953 Oct;55(3):416–421. doi: 10.1042/bj0550416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Prieto J., Barry M., Sherlock S. Serum ferritin in patients with iron overload and with acute and chronic liver diseases. Gastroenterology. 1975 Mar;68(3):525–533. [PubMed] [Google Scholar]
  24. Prough R. A., Masters B. S. Studies on the NADPH oxidase reaction of NADPH-cytochrome C reductase. I. The role of superoxide anion. Ann N Y Acad Sci. 1973;212:89–93. doi: 10.1111/j.1749-6632.1973.tb47588.x. [DOI] [PubMed] [Google Scholar]
  25. Rosen H., Klebanoff S. J. Role of iron and ethylenediaminetetraacetic acid in the bactericidal activity of a superoxide anion-generating system. Arch Biochem Biophys. 1981 May;208(2):512–519. doi: 10.1016/0003-9861(81)90539-7. [DOI] [PubMed] [Google Scholar]
  26. Strobel H. W., Coon M. J. Effect of superoxide generation and dismutation on hydroxylation reactions catalyzed by liver microsomal cytochrome P-450. J Biol Chem. 1971 Dec 25;246(24):7826–7829. [PubMed] [Google Scholar]
  27. Teschke R., Hasumura Y., Lieber C. S. Hepatic microsomal alcohol-oxidizing system. Affinity for methanol, ethanol, propanol, and butanol. J Biol Chem. 1975 Sep 25;250(18):7397–7404. [PubMed] [Google Scholar]
  28. Thurman R. G., Ley H. G., Scholz R. Hepatic microsomal ethanol oxidation. Hydrogen peroxide formation and the role of catalase. Eur J Biochem. 1972 Feb;25(3):420–430. doi: 10.1111/j.1432-1033.1972.tb01711.x. [DOI] [PubMed] [Google Scholar]
  29. Winston G. W., Cederbaum A. I. Oxidative decarboxylation of benzoate to carbon dioxide by rat liver microsomes: a probe for oxygen radical production during microsomal electron transfer. Biochemistry. 1982 Aug 31;21(18):4265–4270. doi: 10.1021/bi00261a013. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES