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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 Cytosol¹

Department of Pharmacology, Morehouse School of Medicine, Atlanta, Georgia 30310

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 ß-naphthylamine. Apparent K_m determinations indicated little difference in NAT affinity (100–300 µM) for any of the substrates between the nine individual bladders. However, the apparent V_max 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 ß-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.

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 5/18/88. Revised 9/ 1/88. Revised 12/27/88. Accepted 1/30/89.

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