Genetic differences in the enzymic properties of the aromatic hydrocarbon inducible N-hydroxylation of 2-acetylaminofluorene in mouse liver.
3-Methylcholanthrene (3-MC) pretreatment induces the liver microsomal 2-acetylaminofluorene (2-AAF) N-hydroxylase activity of C57BL6 responsive mice. The same pretreatment modifies this enzyme by significantly increasing its apparent Km value which, moreover, becomes protein concentration dependent. After 3-MC induction, the C57BL6 mouse liver microsomal 2-AAF N-hydroxylase is activated by paraoxon and 8-hydroxyquinoline. This last chemical does not, however, inhibit the microsomal metabolism of N-hydroxy-2-acetylaminofluorene (N-OH-2-AAF) as it does in the presence of guinea pig liver microsomes. The hypothesis is formulated that 3-MC pretreatment of C57BL6 mice induces not only cytochrome P448 dependent mixed function oxidase but also the synthesis of a microsomal protein which reversibly binds 2-AAF. Mutagenicity data are presented which corroborate this hypothesis. As in guinea pig liver microsomes, N-OH-2-AAF is further metabolized by both C57BL6 and DBA2 mouse liver microsomes. This metabolism is not inhibited by NaF which acts as an inhibitor of microsomal arylamidase. This is a possible contributing reason why 2-AAF is only weakly carcinogenic for mice.
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D006168:Guinea Pigs; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism; D006900:Hydroxylation; D007700:Kinetics; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008862:Microsomes, Liver / Q000201:enzymology*; D013045:Species Specificity
D006881:Hydroxyacetylaminofluorene; D008748:Methylcholanthrene; D015073:2-Acetylaminofluorene; D001189:Aryl Hydrocarbon Hydroxylases