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Metabolic Oxidation of Carcinogenic Arylamines by Rat, Dog, and Human Hepatic Microsomes and by Purified Flavin-containing and Cytochrome P-450 Monooxygenases¹

National Center for Toxicological Research, Jefferson, Arkansas 72079 [G. J. H., C. C. W., F. A. B., F. F. K.], and Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 [F. P. G.]

Hepatic N-oxidation and aryl ring oxidation are generally regarded as critical activation and detoxification pathways for arylamine carcinogenesis. In this study, we examined the in vitro hepatic metabolism of the carcinogens, 2-aminofluorene (2-AF) and 2-naphthylamine (2-NA), and the suspected carcinogen, 1-naphthylamine (1-NA), using high-pressure liquid chromatography. Hepatic microsomes from rats, dogs, and humans were shown to catalyze the N-oxidation of 2-AF and of 2-NA, but not of 1-NA; and the rates of 2-AF N-oxidation were 2- to 3-fold greater than the rates of 2-NA N-oxidation. In each species, rates of 1-hydroxylation of 2-NA and 2-hydroxylation of 1-NA were comparable and were 2- to 5-fold greater than 6-hydroxylation of 2-NA or 5- and 7-hydroxylation of 2-AF. Purified rat hepatic monooxygenases, cytochromes P-450_UT-A, P-450_UT-H, P-450_PB-B, P-450_PB-D, P-450_BNF-B, and P-450_ISF/BNF-G but not P-450_PB-C or P-450_PB/PCN-E, catalyzed several ring oxidations as well as the N-oxidation of 2-AF. Cytochromes P-450_PB-B, P-450_BNF-B, and P-450_ISF/BNF-G were most active; however, only cytochrome P-450_ISF/BNF-G, the isosafrole-induced isozyme, catalyzed the N-oxidation of 2-NA. The purified porcine hepatic flavin-containing monooxygenase, which was known to carry out the N-oxidation of 2-AF, was found to catalyze only ring oxidation of 1-NA and 2-NA. No activity for 1-NA N-oxidation was found with any of the purified enzymes. These data support the hypothesis that 1-NA is probably not carcinogenic. Furthermore, carcinogenic arylamines appear to be metabolized similarly in humans and experimental animals and perhaps selectively by a specific form of hepatic cytochrome P-450. Enzyme mechanisms accounting for the observed product distributions were evaluated by Hückel molecular orbital calculations on neutral, free radical, and cation intermediates. A reaction pathway is proposed that involves two consecutive one-electron oxidations to form a paired substrate cation-enzyme hydroxyl anion intermediate that collapses to ring and N-hydroxy products.

¹ This study was supported by an interagency agreement between the National Institute for Occupational Safety and Health (IA-81-71) and the National Center for Toxicological Research (224-82-0001) and by USPHS Grants ES01590 and CA30907.

² To whom requests for reprints should be addressed.

Received 10/ 2/84. Revised 4/24/85. Accepted 4/30/85.

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