Modifications of hepatic microsomal 9-oxidation of N-2-fluorenylacetamide in response to gonadectomy and treatment of rats with phenobarbital or diethylnitrosamine.
1. The hepatic microsomal 9-hydroxylation of N-2-fluorenylacetamide (2-FAA) is greater in the presence of male, or absence of female, hormones. Thus, 9-hydroxy-2-FAA was the major microsomal metabolite of male rats, which formed 6-fold greater amounts than did female rats. One week after gonadectomy, the amount of 9-hydroxy-2-FAA formed by male rats was decreased by 61%, whereas that formed by female rats was increased 1.4-fold. 2. Treatment of rats with phenobarbital (PB) increased 2- to 3-fold the capacities of hepatic microsomes of both sexes (normal and gonadectomized) for 9-hydroxylation of 2-FAA. 3. Hepatic microsomes of male rats also had greater capacities to form 9-oxo-2-FAA, the metabolite of 9-hydroxy-2-FAA, and 6-hydroxy-2-FAA, a newly identified microsomal metabolite of 2-FAA. These metabolites were also decreased by orchidectomy and induced by PB. 4. 9-Hydroxy-2-FAA was a poor substrate for hepatic microsomal UDP-glucuronyltransferase, and conjugation was not induced by treatment of rats with PB. This indicated retention of 9-hydroxy-2-FAA in the liver and/or further metabolism (e.g. to 9-oxo-2-FAA). 5. The formation of 9-oxo-2-FAA from 2-FAA or 9-hydroxy-2-FAA was increased (1.5-fold) two weeks after treatment of male rats with a single i.p. dose of diethylnitrosamine (200 mg/kg), an initiator of hepatocarcinogenesis. 6. Based on the data we suggest that 9-oxidized metabolites of 2-FAA, the preferential formation of which coincides with the susceptibility of the rat to hepatocarcinogenesis, are promoters.
Malejka-Giganti
D
D
Veterans Administration Medical Center, Minneapolis, Minnesota 55417.
Magat
W J
WJ
Decker
R W
RW
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000818:Animals; D002369:Castration; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004052:Diethylnitrosamine / Q000494:pharmacology*; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009245:NADH Dehydrogenase / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D004052:Diethylnitrosamine; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D009245:NADH Dehydrogenase; D014453:Glucuronosyltransferase; D005966:Glucuronidase; D010634:Phenobarbital