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Perspectives in Cancer Research

Purification of Hepatic Polymorphic Arylamine N-Acetyltransferase from Homozygous Rapid Acetylator Inbred Hamster: Identity with Polymorphic N-Hydroxyarylamine-O-Acetyltransferase

Alma Trinidad, David W. Hein, Timothy D. Rustan, Ronald J. Ferguson, Linda S. Miller, Kyle D. Bucher, Ward G. Kirlin, Fredrick Ogolla and Allen F. Andrews
Alma Trinidad
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David W. Hein
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Timothy D. Rustan
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Ronald J. Ferguson
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Linda S. Miller
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Kyle D. Bucher
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Ward G. Kirlin
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Fredrick Ogolla
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Allen F. Andrews
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DOI:  Published December 1990
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Abstract

The polymorphic acetyltransferase isozyme expressed in homozygous rapid acetylator inbred hamster liver cytosol was purified over 2000-fold by sequential Q-Sepharose fast-flow anion-exchange chromatography, Sephacryl S-200 high-resolution size-exclusion chromatography, Mono Q anion-exchange fast-protein liquid chromatography, and preparative polyacrylamide gel electrophoresis. The isozyme migrated as a single homogeneous monomer following both preparative and sodium dodecyl sulfate-polyacrylamide electrophoresis. The molecular weight was estimated at 34,170 following elution via size-exclusion chromatography and 35,467 following migration via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The homogeneous polymorphic acetyltransferase exhibited a broad substrate specificity; it catalyzed the acetyl coenzyme A-dependent N-acetylation of p-aminobenzoic acid, carbocyclic arylamine carcinogens such as 2-aminofluorene, 4-aminobiphenyl and β-naphthylamine, and heterocyclic arylamine carcinogens such as 2-aminodipyrido[1,2-a:3′2′d]imidazole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. It also readily catalyzed the acetyl coenzyme A-dependent metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene to DNA adducts but not the metabolic activation (via intramolecular, N,O-acetyltransfer) of N-hydroxy-2-acetylaminofluorene or N-hydroxy-4-acetylaminobiphenyl to DNA adducts. Conversely, the partially purified monomorphic acetyltransferase isozyme from the same hamsters readily catalyzed the metabolic activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl, and rates of metabolic activation of these substrates did not differ between homozygous rapid and slow acetylator liver, intestine, kidney, and lung cytosols. Heat inactivation rates for the purified polymorphic acetyltransferase isozyme were first order and indistinguishable for the acetyl coenzyme A-dependent N-acetylation and O-acetylation activities. The results strongly suggest the expression of a single polymorphic acetyltransferase product of the hamster polymorphic acetyltransferase gene that catalyzes both acetyl coenzyme A-dependent N-acetylation and O-acetylation of arylamine and N-hydroxyarylamine carcinogens but not the metabolic activation of N-hydroxy-N-acetylarylamines (arylhydroxamic acids) via intramolecular N,O-acetyltransfer. Consequently, acetylator genotype-dependent metabolic activation of N-hydroxyarylamines to a DNA adduct in hamster is catalyzed by direct O-acetylation of the hydroxyl group and not via sequential N-acetylation followed by N,O-acetyltransfer.

Footnotes

  • ↵1 This work was partially supported by USPHS Grants CA-34627 and RR-08248 (the latter via interagency agreement with the National Cancer Institute). Portions of this work were presented at the 1988 annual meeting of the Federation of American Societies for Experimental Biology (40) and at the Fifth International Conference of the Environmental Mutagen Society (41).

  • ↵3 To whom requests for reprints should be addressed, at Department of Pharmacology, University of North Dakota School of Medicine, 501 North Columbia Road, Grand Forks, ND 58203.

  • ↵4 Graduate student in Molecular Genetics at Georgia State University, Atlanta, GA.

  • Received July 12, 1990.
  • Accepted September 10, 1990.
  • ©1990 American Association for Cancer Research.
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December 1990
Volume 50, Issue 24
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Purification of Hepatic Polymorphic Arylamine N-Acetyltransferase from Homozygous Rapid Acetylator Inbred Hamster: Identity with Polymorphic N-Hydroxyarylamine-O-Acetyltransferase
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Purification of Hepatic Polymorphic Arylamine N-Acetyltransferase from Homozygous Rapid Acetylator Inbred Hamster: Identity with Polymorphic N-Hydroxyarylamine-O-Acetyltransferase
Alma Trinidad, David W. Hein, Timothy D. Rustan, Ronald J. Ferguson, Linda S. Miller, Kyle D. Bucher, Ward G. Kirlin, Fredrick Ogolla and Allen F. Andrews
Cancer Res December 15 1990 (50) (24) 7942-7949;

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Purification of Hepatic Polymorphic Arylamine N-Acetyltransferase from Homozygous Rapid Acetylator Inbred Hamster: Identity with Polymorphic N-Hydroxyarylamine-O-Acetyltransferase
Alma Trinidad, David W. Hein, Timothy D. Rustan, Ronald J. Ferguson, Linda S. Miller, Kyle D. Bucher, Ward G. Kirlin, Fredrick Ogolla and Allen F. Andrews
Cancer Res December 15 1990 (50) (24) 7942-7949;
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