Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Jul;87(14):5499–5503. doi: 10.1073/pnas.87.14.5499

Reductive beta-scission of the hydroperoxides of fatty acids and xenobiotics: role of alcohol-inducible cytochrome P-450.

A D Vaz 1, E S Roberts 1, M J Coon 1
PMCID: PMC54352  PMID: 2371285

Abstract

As shown previously in this laboratory, purified rabbit liver microsomal cytochrome P-450 form 2 (P-450 IIB4) catalyzes the reductive cleavage of hydroperoxides to yield hydrocarbons and either aldehydes or ketones. We have proposed that lipid hydroperoxides are the physiological substrates for the cleavage reaction and have shown that with 13-hydroperoxy-9,11-octadecadienoic acid the formation of pentane is roughly equimolar with respect to the NADPH consumed. In the present study, the other product was isolated and identified as 13-oxo-9,11-tridecadienoic acid. Of particular interest, the alcohol-inducible form of liver microsomal cytochrome P-450 form 3a (P-450 IIE1) is the most active of the isozymes examined in the reductive beta-scission of the 13-hydroperoxide derived from linoleic acid and the 15-hydroperoxide derived from arachidonic acid as well as the model compounds cumyl hydroperoxide (alpha, alpha-dimethylbenzyl hydroperoxide) and t-butyl hydroperoxide. In general, the forms of P-450 with lower activity, as judged by the rate of NADPH oxidation in the reconstituted system, give less of the cleavage products (hydrocarbon and oxo compound) and catalyze direct reduction of the hydroperoxides to the corresponding hydroxy compounds. The occurrence of the reductive cleavage reaction in liver microsomal membranes was demonstrated, and microsomes from animals treated with ethanol or acetone (P-450 IIE1 inducers) or phenobarbital (a P-450 IIB4 inducer) were more active than those from untreated animals. We suggest that the alcohol-inducible P-450, in addition to its known deleterious effects in chemical toxicity and chemical carcinogenesis, may enhance the reductive cleavage of lipid hydroperoxides with a resultant loss in membrane integrity.

Full text

PDF
5501

Images in this article

5501Image
on p.5501

Selected References

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

  1. Black S. D., Coon M. J. P-450 cytochromes: structure and function. Adv Enzymol Relat Areas Mol Biol. 1987;60:35–87. doi: 10.1002/9780470123065.ch2. [DOI] [PubMed] [Google Scholar]
  2. Coon M. J., van der Hoeven T. A., Dahl S. B., Haugen D. A. Two forms of liver microsomal cytochrome P-450, P-450lm2 and P-450LM4 (rabbit liver). Methods Enzymol. 1978;52:109–117. doi: 10.1016/s0076-6879(78)52012-0. [DOI] [PubMed] [Google Scholar]
  3. Das M. L., Orrenius S., Ernster L. On the fatty acid and hydrocarbon hydroxylation in rat liver microsomes. Eur J Biochem. 1968 May;4(4):519–523. doi: 10.1111/j.1432-1033.1968.tb00243.x. [DOI] [PubMed] [Google Scholar]
  4. Delaforge M., Koop D. R., Coon M. J. Role of isosafrole as complexing agent and inducer of P-450LM4 in rabbit liver microsomes. Biochem Biophys Res Commun. 1982 Sep 16;108(1):59–65. doi: 10.1016/0006-291x(82)91831-9. [DOI] [PubMed] [Google Scholar]
  5. Ekström G., Ingelman-Sundberg M. Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem Pharmacol. 1989 Apr 15;38(8):1313–1319. doi: 10.1016/0006-2952(89)90338-9. [DOI] [PubMed] [Google Scholar]
  6. Ellin A., Orrenius S. Hydroperoxide-supported cytochrome P-450-linked fatty acid hydroxylation in liver microsomes. FEBS Lett. 1975 Feb 15;50(3):378–381. doi: 10.1016/0014-5793(75)80532-1. [DOI] [PubMed] [Google Scholar]
  7. French J. S., Coon M. J. Properties of NADPH-cytochrome P-450 reductase purified from rabbit liver microsomes. Arch Biochem Biophys. 1979 Jul;195(2):565–577. doi: 10.1016/0003-9861(79)90383-7. [DOI] [PubMed] [Google Scholar]
  8. Garro A. J., Seitz H. K., Lieber C. S. Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol consumption. Cancer Res. 1981 Jan;41(1):120–124. [PubMed] [Google Scholar]
  9. Garssen G. J., Vliegenthart J. F., Boldingh J. An anaerobic reaction between lipoxygenase, linoleic acid and its hydroperoxides. Biochem J. 1971 Apr;122(3):327–332. doi: 10.1042/bj1220327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Glasgow W. C., Harris T. M., Brash A. R. A short-chain aldehyde is a major lipoxygenase product in arachidonic acid-stimulated porcine leukocytes. J Biol Chem. 1986 Jan 5;261(1):200–204. [PubMed] [Google Scholar]
  11. Goldfinger R., Ahmed K. S., Pitchumoni C. S., Weseley S. A. Concomitant alcohol and drug abuse enhancing acetaminophen toxicity. Report of a case. Am J Gastroenterol. 1978 Oct;70(4):385–388. [PubMed] [Google Scholar]
  12. HOCHSTEIN P., ERNSTER L. ADP-ACTIVATED LIPID PEROXIDATION COUPLED TO THE TPNH OXIDASE SYSTEM OF MICROSOMES. Biochem Biophys Res Commun. 1963 Aug 14;12:388–394. doi: 10.1016/0006-291x(63)90111-6. [DOI] [PubMed] [Google Scholar]
  13. Johansson I., Ingelman-Sundberg M. Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes. Cancer Res. 1988 Oct 1;48(19):5387–5390. [PubMed] [Google Scholar]
  14. Kadlubar F. F., Morton K. C., Ziegler D. M. Microsomal-catalyzed hydroperoxide-dependent C-oxidation of amines. Biochem Biophys Res Commun. 1973 Oct 15;54(4):1255–1261. doi: 10.1016/0006-291x(73)91122-4. [DOI] [PubMed] [Google Scholar]
  15. Koop D. R., Coon M. J. Ethanol oxidation and toxicity: role of alcohol P-450 oxygenase. Alcohol Clin Exp Res. 1986;10(6 Suppl):44S–49S. doi: 10.1111/j.1530-0277.1986.tb05179.x. [DOI] [PubMed] [Google Scholar]
  16. Koop D. R., Crump B. L., Nordblom G. D., Coon M. J. Immunochemical evidence for induction of the alcohol-oxidizing cytochrome P-450 of rabbit liver microsomes by diverse agents: ethanol, imidazole, trichloroethylene, acetone, pyrazole, and isoniazid. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4065–4069. doi: 10.1073/pnas.82.12.4065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Koop D. R., Morgan E. T., Tarr G. E., Coon M. J. Purification and characterization of a unique isozyme of cytochrome P-450 from liver microsomes of ethanol-treated rabbits. J Biol Chem. 1982 Jul 25;257(14):8472–8480. [PubMed] [Google Scholar]
  18. Lieber C. S. Alcohol and the liver: 1984 update. Hepatology. 1984 Nov-Dec;4(6):1243–1260. doi: 10.1002/hep.1840040625. [DOI] [PubMed] [Google Scholar]
  19. Lu A. Y., Junk K. W., Coon M. J. Resolution of the cytochrome P-450-containing omega-hydroxylation system of liver microsomes into three components. J Biol Chem. 1969 Jul 10;244(13):3714–3721. [PubMed] [Google Scholar]
  20. Morgan E. T., Koop D. R., Coon M. J. Comparison of six rabbit liver cytochrome P-450 isozymes in formation of a reactive metabolite of acetaminophen. Biochem Biophys Res Commun. 1983 Apr 15;112(1):8–13. doi: 10.1016/0006-291x(83)91789-8. [DOI] [PubMed] [Google Scholar]
  21. Nebert D. W., Nelson D. R., Adesnik M., Coon M. J., Estabrook R. W., Gonzalez F. J., Guengerich F. P., Gunsalus I. C., Johnson E. F., Kemper B. The P450 superfamily: updated listing of all genes and recommended nomenclature for the chromosomal loci. DNA. 1989 Jan-Feb;8(1):1–13. doi: 10.1089/dna.1.1989.8.1. [DOI] [PubMed] [Google Scholar]
  22. Nordblom G. D., White R. E., Coon M. J. Studies on hydroperoxide-dependent substrate hydroxylation by purified liver microsomal cytochrome P-450. Arch Biochem Biophys. 1976 Aug;175(2):524–533. doi: 10.1016/0003-9861(76)90541-5. [DOI] [PubMed] [Google Scholar]
  23. Peterson F. J., Holloway D. E., Erickson R. R., Duquette P. H., McClain C. J., Holtzman J. L. Ethanol induction of acetaminophen toxicity and metabolism. Life Sci. 1980 Nov 3;27(18):1705–1711. doi: 10.1016/0024-3205(80)90646-3. [DOI] [PubMed] [Google Scholar]
  24. Rahimtula A. D., O'Brien P. J. Hydroperoxide catalyzed liver microsomal aromatic hydroxylation reactions involving cytochrome P-450. Biochem Biophys Res Commun. 1974 Sep 9;60(1):440–447. doi: 10.1016/0006-291x(74)90223-x. [DOI] [PubMed] [Google Scholar]
  25. Sato A., Nakajima T. Enhanced metabolism of volatile hydrocarbons in rat liver following food deprivation, restricted carbohydrate intake, and administration of ethanol, phenobarbital, polychlorinated biphenyl and 3-methylcholanthrene: a comparative study. Xenobiotica. 1985 Jan;15(1):67–75. doi: 10.3109/00498258509045336. [DOI] [PubMed] [Google Scholar]
  26. Sevanian A., Nordenbrand K., Kim E., Ernster L., Hochstein P. Microsomal lipid peroxidation: the role of NADPH--cytochrome P450 reductase and cytochrome P450. Free Radic Biol Med. 1990;8(2):145–152. doi: 10.1016/0891-5849(90)90087-y. [DOI] [PubMed] [Google Scholar]
  27. Stremler K. E., Stafforini D. M., Prescott S. M., Zimmerman G. A., McIntyre T. M. An oxidized derivative of phosphatidylcholine is a substrate for the platelet-activating factor acetylhydrolase from human plasma. J Biol Chem. 1989 Apr 5;264(10):5331–5334. [PubMed] [Google Scholar]
  28. Tuyns A. J. Epidemiology of alcohol and cancer. Cancer Res. 1979 Jul;39(7 Pt 2):2840–2843. [PubMed] [Google Scholar]
  29. Vaz A. D., Coon M. J. Hydrocarbon formation in the reductive cleavage of hydroperoxides by cytochrome P-450. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1172–1176. doi: 10.1073/pnas.84.5.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wendel A., Dumelin E. E. Hydrocarbon exhalation. Methods Enzymol. 1981;77:10–15. doi: 10.1016/s0076-6879(81)77004-6. [DOI] [PubMed] [Google Scholar]
  31. White R. E., Coon M. J. Oxygen activation by cytochrome P-450. Annu Rev Biochem. 1980;49:315–356. doi: 10.1146/annurev.bi.49.070180.001531. [DOI] [PubMed] [Google Scholar]
  32. Yang C. S., Tu Y. Y., Koop D. R., Coon M. J. Metabolism of nitrosamines by purified rabbit liver cytochrome P-450 isozymes. Cancer Res. 1985 Mar;45(3):1140–1145. [PubMed] [Google Scholar]
  33. Zimmerman D. C., Coudron C. A. Identification of Traumatin, a Wound Hormone, as 12-Oxo-trans-10-dodecenoic Acid. Plant Physiol. 1979 Mar;63(3):536–541. doi: 10.1104/pp.63.3.536. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES