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Metabolism of prostaglandin E analogs in guinea pig and rat liver microsomes

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Summary

Tritium-labelled 16,16-dimethyl-PGE2, 9-methylene-PGE2 (9-deoxo-16,16-dimethyl-9-methylene-prostaglandin E2) and tetranor-9-methylene-PGE2 were incubated with guinea pig liver microsomes. All three compounds were converted to ω-oxidized products in yields of a few per cent. In addition, from incubations with 9-methylene-PGE2 and tetranor-9-methylene-PGE2 were also obtained metabolites with the methylene group transformed into a dihydrodiol. In a comparative study with rat liver microsomes, it was found that these converted tetranor-9-methylene-PGE2 in a 50 per cent yield to ω-oxidized products. Finally, 20.000 × G supernatants from guinea pig and rat liver were compared with respect to ω-oxidation. The rat liver 20.000 × G supernatant was found to convert the substrate to the same extent as washed microsomes. By contrast, the guinea pig liver 20.000 × G supernatant was considerably more efficient than washed microsomes.

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References

  1. Israelsson U., Hamberg M. and Samuelsson B. (1969): Biosynthesis of 19-hydroxy-prostaglandin A1, Europ. J. Biochem.,11, 390–394.

    Article  CAS  PubMed  Google Scholar 

  2. Kupfer D., Navarro J. and Piccolo D.E. (1978): Hydroxylation of prostaglandins A1 and E1 by liver microsomal monooxygenase, J. Biol. Chem.,253, 2804–2811.

    CAS  PubMed  Google Scholar 

  3. Samuelsson B., Granstrom E., Green K. and Hamberg M. (1971): Metabolism of prostaglandins, Ann. N.Y. Acad. Sci.,180, 138–163.

    CAS  Google Scholar 

  4. Kupfer D. (1980): Endogenous substrates of monooxygenases: Fatty acids and prostaglandins, Pharmac. Ther.,11, 469–496.

    Article  CAS  Google Scholar 

  5. Kupfer D., Miranda G.K., Navarro J., Piccolo D.E. and Theoharides A.D. (1979): Effect of inducers and inhibitors of monooxygenase on the hydroxylation of prostaglandins in the guinea pig, J. Biol. Chem.,254, 10405–10414.

    CAS  PubMed  Google Scholar 

  6. Theoharides A.D. and Kupfer D. (1981): Evidence for different hepatic microsomal monooxygenases catalyzing ω− and (ω−1)-hydroxylations of prostaglandins E, and E2, J. Biol. Chem.,256, 2168–2175.

    CAS  PubMed  Google Scholar 

  7. Kupfer D., Theoharides A.D. and Miranda G.K. (1980): Differences in hepatic monooxygenase-mediated prostaglandin hydroxylation in rats treated with Aroclor 1254 (PCBs), Firemaster (PBBs), phenobarbital and methylcholanthrene, Fed. Proc.,39, 523 (Abstract 1355).

    Google Scholar 

  8. Orrenius S., Dallner G. and Ernster L. (1964): Inhibition of the TPNH-linked peroxidation of liver microsomes by drugs undergoing oxidative demethylation, Biochem. Biophys. Res. Commun.,14, 329–334.

    Article  CAS  PubMed  Google Scholar 

  9. Jofferey E., Kotake R., el Azhary R. and Mannering G.J. (1977): Effect of linoleic acid hydroperoxide on the hepatic monooxygenase systems of microsomes from untreated, phenobarbital-treated and 3-methylcholanthrene treated rats, Mol. Pharmacol.,13, 415–425.

    Google Scholar 

  10. Little C. and O’Brien P.J. (1968): An intracellular GSHperoxidas with a lipid peroxide substrate, Biochem. Biophys. Res. Commun.,31, 145–150.

    Article  CAS  PubMed  Google Scholar 

  11. Hamberg M. and Samuelsson B. (1971): On the metabolism of prostaglandins E1 and E2 in man, J. Biol. Chem.,246, 6713–6721.

    CAS  PubMed  Google Scholar 

  12. Granstrom E. and Samuelsson B. (1971): On the metabolism of prostaglandin F1α in female subjects, J. Biol. Chem.,246, 7470–7485.

    CAS  PubMed  Google Scholar 

  13. Green K. (1971): The metabolism of prostaglandin F2α in the rat, Biochim. Biophys. Acta,231, 419–444.

    CAS  PubMed  Google Scholar 

  14. Steffenrud S. (1980): Metabolism of 16,16-dimethylprostaglandin E2 in the human female, Biochem. Med.,24, 274–292.

    Article  CAS  PubMed  Google Scholar 

  15. Hansson G. and Granstrom E. (1976): Metabolism of 16,16-dimethyl-prostaglandin F2α in the Cynomolgus monkey and the human female, Biochem. Med.,15, 95–113.

    Article  CAS  PubMed  Google Scholar 

  16. Hansson G. and Granstrom E. (1977): Metabolism of 15-methyl-prostaglandin F2α in the Cynomolgus monkey and the human female, Biochem. Med.,18, 420–439.

    Article  CAS  PubMed  Google Scholar 

  17. Hansson G. (1979): Metabolism of two PGF2α analogues in primates: 15(S)-15-methyl-δ4-cis-PGF1α and 16,16-dimethyl-δ4-cis-PGF1α, Prostaglandins,18, 745–771.

    Article  CAS  PubMed  Google Scholar 

  18. Steffenrud S. (1983): Metabolism of 9-deoxo-16,16-dimethyl-9-methylene prostaglandin E2 in humans, Drug Metab. Dispos.,32, 255–265.

    Google Scholar 

  19. Steffenrud S. (1984): Metabolism of prostaglandin E analogs in the guinea pig liver mitochondrial fraction, Biochem. Med.,32, 161–180.

    Article  CAS  PubMed  Google Scholar 

  20. Steffenrud S. and Lincoln F.H. (1979): Method for quantitative analysis of 16,16-dimethyl-prostaglandin E2 from plasma using deuterated carrier and gas chromatography-mass spectrometry, Anal. Biochem.,100, 109–117.

    Article  CAS  PubMed  Google Scholar 

  21. Norman A. (1953): Separation of conjugated bile acids by partition chromatography. Bile acids and steroids6, Acta Chem. Scand.7, 1413–1419.

    Article  CAS  Google Scholar 

  22. Bergstrom S., Ryhage R., Samuelsson B. and Sjovall J. (1963): Prostaglandins and related factors 15. The structures of prostaglandin E1, F1α and F1π, J. Biol. Chem.,238, 3555–3564.

    CAS  Google Scholar 

  23. Hites R.A. and Biemann K. (1970): Computer evaluation of continuosly scanned mass spectra of gas chromatographic effluents, Anal. Chem.,42, 855–860.

    Article  CAS  Google Scholar 

  24. Green K. (1969): Gas chromatography-mass spectrometry of O-methyloxime derivatives of prostaglandins, Chem. Phys. Lipids,3, 254–272.

    Article  CAS  PubMed  Google Scholar 

  25. Corey E.J. and Venkateswarlu J. (1972): Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives, J. Am. Chem. Soc.,94, 6190–6191.

    Article  CAS  Google Scholar 

  26. Lapworth A. and Mottram E.N. (1925): Oxidation products of oleic acid. Part 1. Conversion of oleic acid into dihydroxy stearic acid and the determination of the higher saturated acids in mixed acids from natural sources, J. Chem. Soc.,127, 1628–1631.

    CAS  Google Scholar 

  27. Malaprade L. (1928): Action des polyalcools sur l’acide perodique. Application analytique, Bull. Soc. Chim.,43, 683–696.

    CAS  Google Scholar 

  28. Bjorkhem I. (1972): On the role of alcohol dehydrogenase in ω — oxidation of fatty acids, Europ. J. Biochem.,30, 441–451.

    Article  CAS  PubMed  Google Scholar 

  29. Middleditch B.S. and Desiderio D.M. (1973): Mass spectra of prostaglandins. IV Trimethylsilyl derivatives of prostaglandins of the F series, Anal. Biochem.,55, 509–520.

    Article  CAS  PubMed  Google Scholar 

  30. Wiberg K.B. and Saegebarth K.A. (1957): The mechanisms of permanganate oxidation. IV Hydroxylation of olefins and related reactions, J. Am. Chem. Soc.,79, 2822–2824.

    Article  CAS  Google Scholar 

  31. Hansson G. (1979): Karolinska Inst. Med. Fac. Doct. Diss.

  32. Bjorkhem I. and Danielsson H. (1970): ω− and (ω−1)-oxidation of fatty acids by rat liver microsomes, Europ. J. Biochem.,17, 450–459.

    Article  CAS  PubMed  Google Scholar 

  33. Jerina D., Daly J., Witkop B., Zaltzmann-Nirenberg P. and Udenfriend S. (1968): Role of the arene-oxepin system in the metabolism of aromatic substrates, Arch. Biochem. Biophys.,128, 176–183.

    Article  CAS  Google Scholar 

  34. Oesch F. (1973): Mammalian epoxide hydrases: Inducible enzymes catalysing inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds, Xenobiotica,3, 305–340.

    Article  CAS  PubMed  Google Scholar 

  35. Bjorkhem I. (1973): ω — oxidation of stearic acid in the normal, starved and diabetic rat liver, Europ. J. Biochem.,40, 415–422.

    Article  CAS  PubMed  Google Scholar 

  36. Burk B.F. (1983): Glutathione-dependent protection by rat liver microsomal protein against lipid peroxidation, Biochim. Biophys. Acta,757, 27–28.

    Google Scholar 

  37. McCay P.B., Gibson D.D., Fong K.L. and Hornbrook K.R. (1976): Effect of glutathione peroxidase activity on lipid peroxidation in biological membranes, Biochim. Biophys. Acta,431, 459–468.

    CAS  Google Scholar 

  38. Burk R.F., Trumble M.J. and Lawrence R.A. (1980): Rat hepatic cytosolic glutathione-dependent enzyme protection against lipid peroxidation in the NADPH-microsomal lipid peroxidation system, Biochim. Biophys. Acta,618, 35–41.

    CAS  PubMed  Google Scholar 

  39. Gibson D.D., Hornbrook K.R. and McCay P.B. (1980): Glutathione-dependant inhibition of lipid peroxidation by a soluble, heat-labile factor in animal tissues, Biochim. Biophys. Acta,620, 572–582.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Chemistry, Karolinska Sjukhuset, Box 60500, S-10401, Stockholm, Sweden

    S. Steffenrud

  2. Department of Chemistry, Karolinska Institutet, Stockholm, Sweden

    S. Steffenrud

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Steffenrud, S. Metabolism of prostaglandin E analogs in guinea pig and rat liver microsomes. European Journal of Drug Metabolism and Pharmacokinetics 11, 39–50 (1986). https://doi.org/10.1007/BF03189774

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  • DOI: https://doi.org/10.1007/BF03189774

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