Metabolism of N-hydroxy-2-acetylaminofluorene and N-hydroxy-phenacetin by guinea pig liver microsomal enzymes.
Deacylation has been proposed as a mechanism of activation of arylhydroxamic acids. In the present studies solubilized preparations from guinea pig liver microsomes, a source of high deacylase activity, were subjected to gel filtration on Sephacryl S-200. A single peak (peak I) of activity was found when column fractions were assayed colorimetrically for deacylation of N-hydroxy-2-acetylaminofluorene (N-OH-AAF). Corresponding to this peak were the following activities: binding of [3H-ring]-N-hydroxy-phenacetin (N-OH-P) to tRNA and deacylation of N-OH-P and N-OH-AAF, measured by the formation of nitrosophenetole (N = O-P) and nitrosofluorene (N = O-F), respectively. The binding of [3H-ring]-N-OH-AAF to tRNA was catalyzed by peak I, but to a greater extent by a second peak (II). The binding of both N-OH-P and N-OH-AAF to tRNA was inhibited by paraoxon, an esterase inhibitor. H.p.l.c. analysis revealed that for peak I, the major ether-extractable metabolites of N-OH-P and N-OH-AAF were the corresponding nitroso derivatives. In the presence of peak II, little metabolism to organic-extractable metabolites occurred. These data indicate that more than one mechanism is involved in the activation of N-OH-P and N-OH-AAF in this system, and that the difference in the activation of these arylhydroxamic acids cannot be explained by differences in the formation of deacylated metabolites.
Vaught
J B
JB
Glowinski
I B
IB
King
C M
CM
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives*; D000104:Acetyl-CoA Hydrolase / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003124:Colorimetry; D005260:Female; D006168:Guinea Pigs; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology*; D010615:Phenacetin / Q000031:analogs & derivatives* / Q000378:metabolism; D012343:RNA, Transfer / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000378:metabolism*
C008068:N-hydroxyphenacetin; D006881:Hydroxyacetylaminofluorene; D012343:RNA, Transfer; D015073:2-Acetylaminofluorene; D013869:Thiolester Hydrolases; D000104:Acetyl-CoA Hydrolase; D010615:Phenacetin