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. 1973 May;70(5):1321–1325. doi: 10.1073/pnas.70.5.1321

Polychlorinated Biphenyls: A New Type of Inducer of Cytochrome P-448 in the Liver

Alvito P Alvares 1,2,*, David R Bickers 1,2, Attallah Kappas 1,2
PMCID: PMC433488  PMID: 4197089

Abstract

The CO-difference spectrum of microsomes from rats treated with the polychlorinated biphenyls mixture, Aroclor 1254, has an absorption maximum at 448 nm. With ethylisocyananide as the ligand for reduced microsomes, Aroclor 1254 treatment causes a shift in the 455-nm peak to 453 nm and increases the ratio of absorbance of 455 nm to that at 430 nm from 0.53, obtained with untreated rats, to 1.24. These findings are similar to those seen in rats treated with the polycyclic hydrocarbon, 3-methylcholanthrene, but differ from those that characterize cytochrome P-450 in control or phenobarbital-treated rats. Aroclor 1254 treatment results in a tripling of cytochrome P-448 content and a 10-fold increase in benzo-[a]pyrene hydroxylation. However—unlike 3-methylcholanthrene, but like the phenobarbital type of inducing agents—Aroclor 1254 treatment causes a significant enhancement of ethylmorphine N-demethylase. These data suggest that Aroclor 1254-induced cytochrome P-448 may be catalytically different from the 3-methylcholanthrene-induced P-448 or that the hemoprotein(s) induced by Aroclor 1254 may be a mixture of cytochromes P-448 and P-450 exhibiting catalytic properties of both cytochromes.

Keywords: cytochrome P-450, rats aryl hydrocarbon hydroxylase, enzyme induction, microsomal enzymes

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Selected References

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

  1. Acker L., Schulte E. Uber das Vorkommen von chlorierten Biphenylen und Hexachlorbenzol neben chlorierten Insektiziden in Humanmilch und menschlichem Fettgewebe. Naturwissenschaften. 1970 Oct;57(10):497–497. doi: 10.1007/BF00593085. [DOI] [PubMed] [Google Scholar]
  2. Allen J. R., Norback D. H. Polychlorinated biphenyl- and triphenyl-induced gastric mucosal hyperplasia in primates. Science. 1973 Feb 2;179(4072):498–499. doi: 10.1126/science.179.4072.498. [DOI] [PubMed] [Google Scholar]
  3. Alvares A. P., Mannering G. J. Two-substrate kinetics of drug-metabolizing enzyme systems of hepatic microsomes. Mol Pharmacol. 1970 May;6(3):206–212. [PubMed] [Google Scholar]
  4. Alvares A. P., Schilling G. R., Kuntzman R. Differences in the kinetics of benzpyrene hydroxylation by hepatic drug-metabolizing enzymes from phenobarbital and 3-methylcholanthrene-treated rats. Biochem Biophys Res Commun. 1968 Mar 12;30(5):588–593. doi: 10.1016/0006-291x(68)90094-6. [DOI] [PubMed] [Google Scholar]
  5. Alvares A. P., Schilling G., Garbut A., Kuntzman R. Studies on the hydroxylation of 3,4-benzpyrene by hepatic microsomes. Effect of albumin on the rate of hydroxylation of 3,4-benzpyrene. Biochem Pharmacol. 1970 Apr;19(4):1449–1455. doi: 10.1016/0006-2952(70)90060-2. [DOI] [PubMed] [Google Scholar]
  6. Alvares A. P., Schilling G., Levin W., Kuntzman R. Alteration of the microsomal hemoprotein by 3-methylcholanthrene: effects of ethionine and actinomycin D. J Pharmacol Exp Ther. 1968 Oct;163(2):417–424. [PubMed] [Google Scholar]
  7. Alvares A. P., Schilling G., Levin W., Kuntzman R. Studies on the induction of CO-binding pigments in liver microsomes by phenobarbital and 3-methylcholanthrene. Biochem Biophys Res Commun. 1967 Nov 30;29(4):521–526. doi: 10.1016/0006-291x(67)90515-3. [DOI] [PubMed] [Google Scholar]
  8. Bache C. A., Serum J. W., Youngs W. D., Lisk D. J. Polychlorinated biphenyl residues: accumulation in Cayuga Lake trout with age. Science. 1972 Sep 29;177(4055):1191–1192. doi: 10.1126/science.177.4055.1191. [DOI] [PubMed] [Google Scholar]
  9. Bickers D. R., Harber L. C., Kappas A., Alvares A. P. Polychlorinated biphenyls: comparative effects of high and low chlorine containing Aroclors on hepatic mixed function oxidase. Res Commun Chem Pathol Pharmacol. 1972 May;3(3):505–512. [PubMed] [Google Scholar]
  10. Bidleman K., Mannering G. J. Induction of drug metabolism. V. Independent formation of cytochromes P-450 and P1-450 in rats treated with phenobarbital and 3-methylcholanthrene simultaneously. Mol Pharmacol. 1970 Nov;6(6):697–701. [PubMed] [Google Scholar]
  11. CONNEY A. H., DAVISON C., GASTEL R., BURNS J. J. Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J Pharmacol Exp Ther. 1960 Sep;130:1–8. [PubMed] [Google Scholar]
  12. CONNEY A. H., MILLER E. C., MILLER J. A. Substrate-induced synthesis and other properties of benzpyrene hydroxylase in rat liver. J Biol Chem. 1957 Oct;228(2):753–766. [PubMed] [Google Scholar]
  13. Conney A. H. Pharmacological implications of microsomal enzyme induction. Pharmacol Rev. 1967 Sep;19(3):317–366. [PubMed] [Google Scholar]
  14. GARFINKEL D. Studies on pig liver microsomes. I. Enzymic and pigment composition of different microsomal fractions. Arch Biochem Biophys. 1958 Oct;77(2):493–509. doi: 10.1016/0003-9861(58)90095-x. [DOI] [PubMed] [Google Scholar]
  15. Imai Y., Sato R. Evidence for two forms of P-450 hemoprotein in microsomal membranes. Biochem Biophys Res Commun. 1966 Apr 6;23(1):5–11. doi: 10.1016/0006-291x(66)90260-9. [DOI] [PubMed] [Google Scholar]
  16. Imai Y., Sato R. Substrate interaction with hydroxylase system in liver microsomes. Biochem Biophys Res Commun. 1966 Mar 22;22(6):620–626. doi: 10.1016/0006-291x(66)90191-4. [DOI] [PubMed] [Google Scholar]
  17. Jensen S., Johnels A. G., Olsson M., Otterlind G. DDT and PCB in marine animals from Swedish waters. Nature. 1969 Oct 18;224(5216):247–250. doi: 10.1038/224247a0. [DOI] [PubMed] [Google Scholar]
  18. KLINGENBERG M. Pigments of rat liver microsomes. Arch Biochem Biophys. 1958 Jun;75(2):376–386. doi: 10.1016/0003-9861(58)90436-3. [DOI] [PubMed] [Google Scholar]
  19. Koeman J. H., ten Noever de Brauw M. C., de Vos R. H. Chlorinated biphenyls in fish, mussels and birds from the River Rhine and the Netherlands coastal area. Nature. 1969 Mar 22;221(5186):1126–1128. doi: 10.1038/2211126a0. [DOI] [PubMed] [Google Scholar]
  20. Lincer J. L., Peakall D. B. Metabolic effects of polychlorinated biphenyls in the American kestrel. Nature. 1970 Nov 21;228(5273):783–784. doi: 10.1038/228783a0. [DOI] [PubMed] [Google Scholar]
  21. Litterst C. L., Farber T. M., Baker A. M., Van Loon E. J. Effect of polychlorinated biphenyls on hepatic microsomal enzymes in the rat. Toxicol Appl Pharmacol. 1972 Sep;23(1):112–122. doi: 10.1016/0041-008x(72)90210-4. [DOI] [PubMed] [Google Scholar]
  22. Lu A. Y., Kuntzman R., West S., Jacobson M., Conney A. H. Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds, and endogenous substrates. II. Role of the cytochrome P-450 and P-448 fractions in drug and steroid hydroxylations. J Biol Chem. 1972 Mar 25;247(6):1727–1734. [PubMed] [Google Scholar]
  23. Nebert D. W., Gelboin H. V. Substrate-inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme. J Biol Chem. 1968 Dec 10;243(23):6242–6249. [PubMed] [Google Scholar]
  24. OMURA T., SATO R. THE CARBON MONOXIDE-BINDING PIGMENT OF LIVER MICROSOMES. I. EVIDENCE FOR ITS HEMOPROTEIN NATURE. J Biol Chem. 1964 Jul;239:2370–2378. [PubMed] [Google Scholar]
  25. Price H. A., Welch R. L. Occurrence of polychlorinated biphenyls in humans. Environ Health Perspect. 1972 Apr;1:73–78. doi: 10.1289/ehp.720173. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Remmer H., Schenkman J., Estabrook R. W., Sasame H., Gillette J., Narasimhulu S., Cooper D. Y., Rosenthal O. Drug interaction with hepatic microsomal cytochrome. Mol Pharmacol. 1966 Mar;2(2):187–190. [PubMed] [Google Scholar]
  27. Risebrough R. W., Rieche P., Peakall D. B., Herman S. G., Kirven M. N. Polychlorinated biphenyls in the global ecosystem. Nature. 1968 Dec 14;220(5172):1098–1102. doi: 10.1038/2201098a0. [DOI] [PubMed] [Google Scholar]
  28. Shoeman D. W., Chaplin M. D., Mannering G. J. Induction of drug metabolism. 3. Further information of a new P-450 hemoprotein after treatment of rats with 3-methylcholanthrene. Mol Pharmacol. 1969 Jul;5(4):412–419. [PubMed] [Google Scholar]
  29. Sladek N. E., Mannering G. J. Evidence for a new P-450 hemoprotein in hepatic microsomes from methylcholanthrene treated rats. Biochem Biophys Res Commun. 1966 Sep 8;24(5):668–674. doi: 10.1016/0006-291x(66)90376-7. [DOI] [PubMed] [Google Scholar]
  30. Sladek N. E., Mannering G. J. Induction of drug metabolism. II. Qualitative differences in the microsomal N-demethylating systems stimulated by polycyclic hydrocarbons and by phenobarbital. Mol Pharmacol. 1969 Mar;5(2):186–199. [PubMed] [Google Scholar]
  31. Yobs A. R. Levels of polychlorinated biphenyls in adipose tissue of the general population of the nation. Environ Health Perspect. 1972 Apr;1:79–81. doi: 10.1289/ehp.720179. [DOI] [PMC free article] [PubMed] [Google Scholar]

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