Skip to main content
NCBI home page
Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1988 Nov;79(11):1159–1167. doi: 10.1111/j.1349-7006.1988.tb01540.x

Metabolic Activation of Pyrolysate Arylamines by Human Liver Microsomes; Possible Involvement of a P‐448‐H Type Cytochrome P‐450

Yasushi Yamazoe 1,✉, Medhat Abu‐Zeid 1, Kiyomi Yamauchi 1, Ryuichi Kato 1
PMCID: PMC5917648  PMID: 3147272

Abstract

Metabolic activating capacity of human livers for carcinogenic heterocyclic arylamines has been studied using a Salmonella mutagenesis test. A large individual variation was observed among 15 liver samples in the capacities of activation of Glu‐P‐1(2‐amino‐6‐methyldipyrido[1,2‐α:3′,2′‐d]imidazole), IQ (2‐amino‐3‐methylimidazo[4,5‐f]quinoline) and MeIQx (2‐amino‐3,8‐dimethyl‐3H‐imidazo[4,5‐f]quinoxaline). The average numbers of revertants induced by the three heterocyclic arylamines were nearly the same or rather higher in the presence of hepatic microsomes from human than those from rat. In high‐performance liquid chromatography, formation of N‐hydroxy‐Glu‐P‐1 was detected and accounted for more than 80% of the total mutagenicity observed in the human microsomal system with Glu‐P‐1, indicating that, similarly to experimental animals, N‐hydroxylation is a major activating step for heterocyclic arylamines in human. Addition of flavone or 7,8‐benzoflavone to human liver microsomes showed effective inhibition of the mutagenic activation of Glu‐P‐1, although the treatment rather enhanced microsomal benzo[a]pyrene hydroxylation in human livers. Mutagenic activation of Glu‐P‐1 by human liver microsomes was also decreased by the inclusion of anti‐rat P‐448‐H IgG, and was well correlated with the content of immunoreactive P‐448‐H in livers, suggesting the involvement of a human cytochrome P‐450, which shares immunochemical and catalytic properties with rat P‐448‐H, in the metabolic activation of heterocyclic arylamines in human livers.

Keywords: Human P‐448‐H, Glu‐P‐1, IQ, MeIQx

Full Text

The Full Text of this article is available as a PDF (482.2 KB).

References

  • 1. ) Kamataki , T. , Maeda , K. , Yamazoe , Y. , Matsuda , N. , Ishii , K. and Kato , R.A high spin form of cytochrome P‐450 highly purified from polychlorinated biphenyl‐treated rats: catalytic characterization and immunochemical quantitation in liver microsomes . Mol. Pharmacol. , 24 , 146 – 155 ( 1983. ). [PubMed] [Google Scholar]
  • 2. ) Sugimura , T. and Sato , S.Mutagenscarcinogens in foods . Cancer Res. ( Suppl. ), 432415(s) – 2421(s) ( 1983. ). [PubMed] [Google Scholar]
  • 3. ) Doll , R. and Peto , R.Quantitative estimates of available risks of cancer in the United States today . J. Natl. Cancer Inst. , 66 , 1191 – 1308 ( 1981. ). [PubMed] [Google Scholar]
  • 4. ) Nagao , M. , Wakabayashi , K. and Sugimura , T.Mutagens in food and drinks, and their carcinogenicity . In “ Mutagenicity Testing in Environmental Pollution Control ,” 19th Ed. , ed. Zimmermann F. K. and Taylor‐Mayer R. E. , pp. 69 – 85 ( 1985. ). Ellis Horwood Ltd. , Chichester . [Google Scholar]
  • 5. ) Sugimura , T. , Sato , S. , Ohgaki , H. , Takayama , S. , Nagao , M. and Wakabayashi , K.Mutagens and carcinogens in cooked foods . In “ Genetic Toxicology of the Diet ,” ed. Knudsen I. , pp. 85 – 107 ( 1986. ). Alan R. Liss Inc. , New York . [PubMed] [Google Scholar]
  • 6. ) Kato , R.Metabolic activation of mutagenic heterocyclic aromatic amines from protein pyrolysates . CRC Crit. Rev. Toxicol. , 16 , 307 – 348 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 7. ) Kato , R. , Yamazoe , Y. and Kamataki , T.Metabolic activation of tryptophan pyrolysates, Trp‐P‐1 and Trp‐P‐2 by hepatic cytochrome P‐450 . In “ Genetic and Environmental Factors in Experimental and Human Cancer ,” ed. Gelboin H. V. , Macmahon B. , Matsushima T. , Sugimura T. , Takayama S. and Takebe H. , pp. 79 – 87 ( 1980. ). Japan Sci. Soc. Press; , Tokyo . [Google Scholar]
  • 8. ) Wislocki , P. G. , Miwa , G. T. and Lu , A. Y. H.Reactions catalyzed by the cytochrome P‐450 system . In “ Enzymatic Basis of Detoxication ,” ed. Jakoby W. B. , Vol. 1 , pp. 135 – 182 ( 1980. ). Academic Press; , New York . [Google Scholar]
  • 9. ) Kato , R. , Kamataki , T. and Yamazoe , Y.Hydroxylation of carcinogenic and mutagenic aromatic amines . Environ. Health Perspect. , 49 , 21 – 25 ( 1983. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. ) Ishii , K. , Yamazoe , Y. , Kamataki , T. and Kato , R.Metabolic activation of glutamic acid pyrolysis products, 2‐amino‐6‐methyldipyrido[l,2‐a:3′,2′‐d]imidazole and 2‐aminodipyrido[1,2‐a:3′,2′‐d]imidazole, by purified cytochrome P‐450 . Chem.-Biol. Interact. , 38 , 1 – 13 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Yamazoe , Y. , Shimada , M. , Kamataki , T. and Kato , R.Microsomal activation of 2‐amino‐3‐methylimidazo[4,5‐f]quinoline, a pyrolysate of sardine and beef extracts, to mutagenic intermediate . Cancer Res. , 43 , 5768 – 5774 ( 1983. ). [PubMed] [Google Scholar]
  • 12. ) Yamazoe , Y. , Abu‐Zeid , M. , Manabe , S. , Toyama , S. and Kato , R.Metabolic activation of a protein pyrolysate promutagen 2‐amino‐3,8‐dimethylimidazo[4,5‐f]quinoxaline (MeIQx) by rat liver microsomes and purified cytochrome P‐450 . Carcinogenesis , 9 , 105 – 109 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Kato , R. and Yamazoe , Y.Metabolic activation and covalent binding to nucleic acids of carcinogenic heterocyclic amines from cooked foods and amino acid pyrolysates . Jpn. J. Cancer Res. (Gann) , 78 , 297 – 311 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Quattrochi , L. C. , Pendurthi , U. R. , Okino , S. T. , Potenza , C. and Tukey , R. H.Human cytochrome P‐450 4 mRNA and gene: part of a multigene family that contains Alu sequences in its mRNA . Proc. Natl. Acad. Sci. USA , 83 , 6731 – 6735 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. ) Ekstrom , G. , Bahr , C. V. , Glaumann , H. and Ingelman‐Sundberg , M.Interindividual variation in benzo[a]pyrene metabolism and composition of isoenzymes of cytochrome P‐450 as revealed by SDS‐gel electrophoresis of human liver microsomal fractions . Acta Pharmacol. Toxicol. , 50 , 251 – 260 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 16. ) Kremers , P. , Beaune , P. , Cresteil , T. , De Graeve , J. , Columelli , S. , Leroux , J. P. and Gielen , J. E.Cytochrome P‐450 monooxygenase activity in human and rat liver microsomes . Eur. J. Biochem. , 118 , 599 – 606 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 17. ) Jakobsson , S. W. , Okita , R. T. , Mock , N. J. , Masters , B. S. S. , Buja , L. M. and Prough , R. A.Monooxygenase activities of human liver, lung and kidney microsomes: a study of 42 post‐mortem cases . Acta Pharmacol. Toxicol. , 50 , 332 – 341 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Davies , D. S. , Kahn , G. C. , Murray , S. , Brodie , M. J. and Boobis , A. R.Evidence for an enzymatic defect in the 4‐hydroxylation of debrisoquine by human liver . Br. J. Clin. Pharmacol. , 11 , 89 – 91 ( 1981. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. ) Eichelbaum , M. , Spannbrucker , N. and Dengler , H. J.A probable genetic defect of the metabolism of sparteine . In “ Biological Oxidation of Nitrogen ,” ed. Gorrod J. W. , pp. 113 – 118 ( 1977. ). Elsevier/North‐Holland Biomedical Press; , Amsterdam . [Google Scholar]
  • 20. ) Eichelbaum , M.Defective oxidation of drugs: pharmacokinetic and therapeutic implications . Clin. Pharmacokinet. , 7 , 1 – 22 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 21. ) Kato , R. , Yamazoe , Y. , Shimada , M. , Murayama , N. and Kamataki , T.Effect of growth hormone and ectopic transplantation of pituitary gland on sex‐specific forms of cytochrome P‐450 and testosterone and drug oxidation in rat liver . J. Biochem. , 100 , 895 – 902 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 22. ) Kamataki , T. , Maeda , K. , Yamazoe , Y. , Nagai , T. and Kato , R.Partial purification and characterization of cytochrome P‐450 responsible for sex difference in drug metabolism in the rat . Biochem. Biophys. Res. Commun. , 103 , 1 – 7 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 23. ) Kamataki , T. , Maeda , K. , Shimada , M. , Kitani , K. , Nagai , T. and Kato , R.Age related alteration in the activities of drugmetabolising enzymes and components of sex‐specific forms of P‐450 in liver microsomes from male and female rats . J. Pharmacol. Exp. Ther. , 233 , 222 – 228 ( 1985. ). [PubMed] [Google Scholar]
  • 24. ) Yamazoe , Y. , Kamataki , T. and Kato , R.Species difference in N‐hydroxylation of a tryptophan pyrolysis product in relation to mutagenic activation . Cancer Res. , 41 , 4518 – 4522 ( 1981. ). [PubMed] [Google Scholar]
  • 25. ) Lowry , O. H. , Rosebrough , N. J. , Farr , A. L. and Randall , R. J.Protein measurement with the Folin phenol reagent . J. Biol. Chem. , 193 , 265 – 275 ( 1951. ). [PubMed] [Google Scholar]
  • 26. ) Omura , T. and Sato , R.The carbon monoxide‐binding pigment of liver microsomes: solublization, purification and properties . J. Biol. Chem. , 239 , 2379 – 2385 ( 1964. ). [PubMed] [Google Scholar]
  • 27. ) Omura , T. and Takesue , S.A new method for simultaneous purification of cytochrome b5 and NADPH‐cytochrome c reductase from rat liver microsomes . J. Biochem. , 67 , 249 – 257 ( 1970. ). [DOI] [PubMed] [Google Scholar]
  • 28. ) Phillips , A. V. and Langdon , R. G.Hepatictriphosphopyridine nucleotide cytochrome c reductase: isolation, characterization and kinetic studies . J. Biol. Chem. , 237 , 2652 – 2660 ( 1962. ). [PubMed] [Google Scholar]
  • 29. ) Nebert , D. W. and Gelboin , H. V.Substrate inducible microsomal aryl hydroxylase in mammalian cell culture: assay and properties of induced eyzyme . J. Biol. Chem. , 243 , 6242 – 6249 ( 1968. ). [PubMed] [Google Scholar]
  • 30. ) Ames , B. N. , McCann , M. and Yamasaki , E.Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsomes mutagenicity test . Mutat. Res. , 31 , 347 – 363 ( 1975. ). [DOI] [PubMed] [Google Scholar]
  • 31. ) Yamazoe , Y. , Ishii , K. , Kamataki , T. , Kato , R. and Sugimura , T.Isolation and characterization of active metabolite of tryptophanpyrolysate mutagen, Trp‐P‐2 formed by rat liver microsomes . Chem.-Biol. Interact. , 30 , 125 – 138 ( 1980. ). [DOI] [PubMed] [Google Scholar]
  • 32. ) Diamond , L. and Gelboin , H. V.Alphanaphthoflavone: an inhibitor of hydrocarbon cytotoxicity and microsomal hydroxylase . Science , 168 , 1023 – 1025 ( 1969. ). [DOI] [PubMed] [Google Scholar]
  • 33. ) Lesca , P. , Rafidinarivo , E. , Lecointe , P. and Mansuy , D.A class of strong inhibitors of microsomal monooxygenases. The ellipticines . Chem.-Biol. Interact. , 24 , 189 – 198 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 34. ) Saito , K. , Yamazoe , Y. , Kamataki , T. and Kato , R.Syntheses of hydroxyamino, nitroso and nitro derivatives of Trp‐P‐2 and Glu‐P‐1, amino acid pyrolysate mutagens, and their direct mutagenicities towards Salmonella typhimurium TA98 and TA98NR . Carcinogenesis , 4 , 1547 – 1550 ( 1983. ). [DOI] [PubMed] [Google Scholar]
  • 35. ) Noshiro , M. and Omura , T.Immunochemical study on the electron pathway from NADH to cytochrome P‐450 of liver microsomes . J. Biochem. , 83 , 61 – 77 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 36. ) Yamazoe , Y. , Shimada , M. , Murayama , N. and Kato , R.Suppression of levels of phenobarbital‐inducible rat liver cytochrome P‐450 by pituitary hormone . J. Biol. Chem. , 262 , 7423 – 7428 ( 1987. ). [PubMed] [Google Scholar]
  • 37. ) Kapitulnik , J. , Poppers , P. J. , Buening , M. K. , Fortner , J. B. and Conney , A. H.Activation of monooxygenases in human liver by 7,8‐benzoflavone . Clin. Pharmacol. Ther. , 22 , 475 – 484 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 38. ) Manabe , S. , Yanagisawa , H. , Ishikawa , S. , Kitagawa , Y. , Kanai , Y. and Wada , O.Accumulation of 2‐amino‐6‐methyldipyrido[1,2‐a:3′,2′‐d]imidazole and 2‐aminodipyrido‐[1,2‐a:3′,2′‐d]imidazole, carcinogenic glutamic acid pyrolysis products, in plasma of patients with uremia . Cancer Res. , 47 , 6150 – 6155 ( 1987. ). [PubMed] [Google Scholar]
  • 39. ) Yanagisawa , H. , Manabe , S. , Kitagawa , Y. , Ishikawa , S. , Nakajima , K. and Wada , O.Presence of 2‐amino‐3,8‐dimethylimidazo‐[4,5f]quinoxaline (MeIQx) in dialysate from patients with uremia . Biochem. Biophys. Res. Commun. , 138 , 1084 – 1089 ( 1986. ). [DOI] [PubMed] [Google Scholar]
  • 40. ) McManus , M. E. , Stupans , I. , Ioannoni , B. , Burgess , W. , Robson , R. A. and Birkett , D. J.Identification and quantitation in human liver of cytochrome P‐450 analogous to rabbit cytochromes P‐450 forms 4 and 6 . Xenobiotica , 18 , 207 – 216 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 41. ) Jaiswal , A. K. , Nebert , D. W. and Gonzalez , F. J.Human P3450: cDNA and complete amino acid sequence . Nucleic Acids Res. , 14 , 6773 – 6774 ( 1986. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42. ) Yamazoe , Y. , Abu‐Zeid , M. , Yamauchi , K. , Murayama , N. , Shimada , M. and Kato , R.Enhancement by alloxan‐induced diabetes of the rate of metabolic activation of three pyrolysate carcinogens via increase in the P‐448‐H content in rat liver . Biochem. Pharmacol. , 37 , 2503 – 2506 ( 1988. ). [DOI] [PubMed] [Google Scholar]

Articles from Japanese Journal of Cancer Research : Gann are provided here courtesy of Wiley

RESOURCES