Species differences in the biochemical properties of liver microsomal arylamine and arylamide n-hydroxylases.
Cytochrome P-448 dependent microsomal N-hydroxylases are key enzymes in the metabolic activation of both arylamides and arylamines. Using 2-acetylaminofluorene (2-AAF) and 2-aminofluorene (2-AF) as substrates, the present report compares the biochemical properties of rat, hamster and mouse liver N-hydroxylases. There are marked species differences both in terms of the affinity for the two substrates and in terms of maximum velocity of the enzymes. The rat and hamster liver arylamide N-hydroxylases are induced by pretreatment with 2-AAF which also significantly increases their affinity for the substrate. In mouse liver neither arylamide nor arylamine N-hydroxylases are modified or induced. With 2-AF as substrate, arylamide treatment never enhances N-hydroxylation but it reduces the Km-value of the rat and hamster liver enzymes. Among the effectors tested in vitro, 3-methylcholanthrene (3-MC), 7,8-benzoflavone (BF), benzo[a]pyrene (B[a]P) and miconazole (MN) inhibit hepatic arylamide N-hydroxylase in the submicromolar range. Harman (H) and paraoxon (PX) act in a dose-dependent manner in the micromolar range and metyrapone (MP) is not an inhibitor even at 50-microM concentration. Among the position isomers, 1- and 3-AAF are inhibitors of the N-hydroxylating enzymes whereas 4-AAF is not.
D015073:2-Acetylaminofluorene / Q000378:metabolism; D000818:Animals; D001564:Benzo(a)pyrene; D001571:Benzoflavones / Q000494:pharmacology; D001580:Benzopyrenes / Q000494:pharmacology; D006224:Cricetinae; D005449:Fluorenes / Q000378:metabolism; D007536:Isomerism; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D051379:Mice; D008825:Miconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010261:Paraoxon / Q000494:pharmacology; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity
D001571:Benzoflavones; D001580:Benzopyrenes; D005449:Fluorenes; D001564:Benzo(a)pyrene; C012177:2-aminofluorene; D008748:Methylcholanthrene; D008825:Miconazole; D015073:2-Acetylaminofluorene; D006899:Mixed Function Oxygenases; C030541:arylamide N-hydroxylase; C035198:arylamine N-hydroxylase; D010261:Paraoxon; D008797:Metyrapone