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Basic Sciences

Polymorphic Expression of Acetyl Coenzyme A-dependent Arylamine N-Acetyltransferase and Acetyl Coenzyme A-dependent O-Acetyltransferase-mediated Activation of N-Hydroxyarylamines by Human Bladder Cytosol

Ward G. Kirlin, Alma Trinidad, Tokunbo Yerokun, Fredrick Ogolla, Ronald J. Ferguson, Allen F. Andrews, Pamela K. Brady and David W. Hein
Ward G. Kirlin
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Alma Trinidad
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Tokunbo Yerokun
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Fredrick Ogolla
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Ronald J. Ferguson
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Allen F. Andrews
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Pamela K. Brady
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David W. Hein
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DOI:  Published May 1989
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Abstract

Human epidemiological studies suggest a genetic predisposition to bladder cancer among slow N-acetylators. The capacity of human bladder to N-acetylate arylamines, catalyzed by acetyl coenzyme A-dependent N-acetyltransferase(s) (EC 2.3.1.5) (NAT), may be an important step in the activation and/or deactivation of arylamines in the pathways leading to the initiation of bladder cancer. Another possible activation step is the direct O-acetylation of N-hydroxyarylamines via O-acetyltransferase(s) (OAT) to DNA-binding electrophiles. Human bladder cytosol from nine fresh autopsy specimens were investigated for NAT activity towards p-aminobenzoic acid, and the arylamine carcinogens 4-aminobiphenyl, 2-aminofluorene, and β-naphthylamine. Apparent Km determinations indicated little difference in NAT affinity (100–300 µm) for any of the substrates between the nine individual bladders. However, the apparent Vmax determinations indicated that the bladders could be classified into rapid or slow acetylator phenotypes based on their NAT activity towards 4-aminobiphenyl, 2-aminofluorene, and β-naphthylamine. Four of the bladder cytosols had mean activities significantly (P < 0.01) higher (approximately 10-fold) than the mean NAT activities of the other five bladder cytosols towards each arylamine carcinogen. However, no significant difference was detected in their NAT activities using p-aminobenzoic acid as a substrate. The human bladder cytosols were also tested for their capacity to activate N-hydroxy-3,2′-dimethyl-4-aminobiphenyl to a DNA-binding electrophile through a direct OAT-mediated catalysis. The N-hydroxyarylamine OAT activity also discriminated between two levels of activation, being significantly (P = 0.0002) higher (about twofold) in the rapid N-acetylator bladder cytosols, that correlated (r = 0.94) with the measured levels of NAT activity in each bladder cytosol. These results suggest that NAT activity and OAT activity of the human bladder vary concordantly with N-acetylator phenotype. The polymorphic expression of these acetylation activities may be important risk factors in human susceptibility to bladder cancer from arylamine carcinogens.

Footnotes

  • ↵1 This work was supported in part by U. S. Public Health Service Grants CA-34627 and RR-08248 from the National Institutes of Health/National Cancer Institute. Preliminary reports of this work were presented to the 1987 Third International Conference on Carcinogenic and Mutagenic N-Substituted Aryl Compounds, Dearborn, MI (see Ref. 40, pp. 149–153), the 1988 annual meeting of the American Association for Cancer Research, New Orleans, LA (Proc. Amer. Assoc. Cancer Res. 29: 118, 1988), and the 1988 annual meeting of the American Society of Pharmacology and Experimental Therapeutics, Montreal, Quebec, (The Pharmacologist 30: A76, 1988).

  • ↵2 To whom reprint requests should be sent, at Department of Pharmacology, Morehouse School of Medicine, 720 Westview Drive, SW Atlanta, GA 30310-1495.

  • ↵3 Supported by a National Research Service Award (GM-07808) in Biochemistry at Atlanta University.

  • ↵4 Supported by NIH Grant RR-08248 via interagency agreement with the National Cancer Institute.

  • ↵5 Holds adjunct faculty appointment in the Department of Pharmacology, Emory University School of Medicine, Department of Chemistry, Georgia State University, and the Department of Biology, Atlanta University, Atlanta, GA.

  • Received May 18, 1988.
  • Revision received September 1, 1988.
  • Revision received December 27, 1988.
  • Accepted January 30, 1989.
  • ©1989 American Association for Cancer Research.
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May 1989
Volume 49, Issue 9
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Polymorphic Expression of Acetyl Coenzyme A-dependent Arylamine N-Acetyltransferase and Acetyl Coenzyme A-dependent O-Acetyltransferase-mediated Activation of N-Hydroxyarylamines by Human Bladder Cytosol
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Polymorphic Expression of Acetyl Coenzyme A-dependent Arylamine N-Acetyltransferase and Acetyl Coenzyme A-dependent O-Acetyltransferase-mediated Activation of N-Hydroxyarylamines by Human Bladder Cytosol
Ward G. Kirlin, Alma Trinidad, Tokunbo Yerokun, Fredrick Ogolla, Ronald J. Ferguson, Allen F. Andrews, Pamela K. Brady and David W. Hein
Cancer Res May 1 1989 (49) (9) 2448-2454;

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Polymorphic Expression of Acetyl Coenzyme A-dependent Arylamine N-Acetyltransferase and Acetyl Coenzyme A-dependent O-Acetyltransferase-mediated Activation of N-Hydroxyarylamines by Human Bladder Cytosol
Ward G. Kirlin, Alma Trinidad, Tokunbo Yerokun, Fredrick Ogolla, Ronald J. Ferguson, Allen F. Andrews, Pamela K. Brady and David W. Hein
Cancer Res May 1 1989 (49) (9) 2448-2454;
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