Induction of ornithine decarboxylase and augmentation of tyrosine aminotransferase activity by N-hydroxy-2-acetylaminofluorene and 2-acetylaminofluorene in rat liver. Influence of sex, retinylacetate, indomethacin, and pentachlorophenol.
IP injection in rats of 2-acetylaminofluorene (AAF) or N-hydroxy-2-acetylaminofluorene (N-OH-AAF) resulted in a transient increase of hepatic ornithine decarboxylase (ODC) and tyrosine aminotransferase (TAT) activity. Maximal activity of ODC was observed 4 hr and of TAT 3 hr after administration of either AAF or N-OH-AAF. A lag-time of 2 hr preceded the increase of ODC and TAT activity. N-OH-AAF dependent ODC induction displayed an almost linear dose-response in the dose range up to 94.1 mumol/kg bw (body weight) when the ODC activity was measured at its maximum 4 hr after administration. Elevation of the dose N-OH-AAF to 126 mol/kg bw resulted in a lower ODC induction. Administration of doses AAF to 31.4 mumol did not change ODC activity. At doses up to 126 mumol/kg bw ODC induction increased linear. TAT induction increased linear in the dose range 15.7-94.1 mumol N-OH-AAF and 31.4-94.1 mumol AAF/kg. Lowering the dose of AAF did not result in a lower ODC or TAT activity. Judged by the effects of actinomycin D or cycloheximide administered 1 hr prior to AAF or N-OH-AAF, the in vivo induction of rat liver ODC activity by AAF and N-OH-AAF appeared to be under transcriptional control, whereas augmentation of TAT activity under influence of AAF or N-OH-AAF appeared the result of (post) translational events. Induction of ODC by AAF or N-OH-AAF was not significantly changed by indomethacin, was slightly increased by pentachlorophenol (PCP) and was synergistically enhanced by retinylacetate (RA). The increase of TAT activity was stimulated by PCP and RA. The effect of PCP indicates that N-sulfonoxy-2-acetylaminofluorene is most probably not involved in the induction of ODC. AAF appeared more effective hepatic ODC inducer in females than males and moreover more effective than N-OH-AAF in females. N-OH-AAF had stronger ODC inducing capacity in males than females. Similar observations were made with respect to TAT activity. When induction of ODC is indicative for a tumor promoting property then the data presented here suggest that tumor promotion of the complete carcinogens AAF and N-OH-AAF is not mediated by N-O-sulfation; this might be due to other metabolic conversions.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D006881:Hydroxyacetylaminofluorene / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008099:Liver / Q000201:enzymology*; D008297:Male; D009955:Ornithine Decarboxylase / Q000096:biosynthesis*; D010416:Pentachlorophenol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D000084562:Retinyl Esters; D012737:Sex Factors; D014444:Tyrosine Transaminase / Q000096:biosynthesis*; D014801:Vitamin A / Q000031:analogs & derivatives / Q000494:pharmacology
D004224:Diterpenes; D000084562:Retinyl Esters; D014801:Vitamin A; D003609:Dactinomycin; C009166:retinol acetate; D006881:Hydroxyacetylaminofluorene; D003994:Bucladesine; D003513:Cycloheximide; D015073:2-Acetylaminofluorene; D010416:Pentachlorophenol; D014444:Tyrosine Transaminase; D009955:Ornithine Decarboxylase; D007213:Indomethacin