Cyclic modulation of enzymes of pyrimidine nucleotide biosynthesis precedes sialoglycoconjugate changes during 2-acetylaminofluorene-induced hepatocarcinogenesis in the rat.
Three enzymatic activities associated with pyrimidine nucleotide biosynthesis were monitored at weekly or bi-weekly intervals during 2-acetylaminofluorene- (0.025% in a Farber Basal Carcinogenic diet) induced hepatocarcinogenesis in the rat. Dihydroorotate dehydrogenase, the fourth of six enzymes in de novo pyrimidine biosynthesis, declined in activity while UDP kinase and CTP synthetase showed sequential increases in activity. The alterations in activity appeared to be cyclic, followed by a full or partial return to control values. Three full cycles were monitored. The first cycle preceded nodule formation. The second cycle accompanied nodule formation and preceded sialoglycoconjugate changes reported previously. The third cycle accompanied the early glycoconjugate changes. The cyclic pattern was reproducible in three separate experiments. In each cycle, the order of events was as follows: decrease in dihydroorotate dehydrogenase, sequential increases in UDP kinase, CTP synthetase and CMPsialic acid synthase, and finally increases in the enzyme lactosylceramide: CMPsialic acid sialyltransferase, lipid-soluble sialic acid and total sialic acid. In livers of animals fed 1.87% of the hepatotoxin, 4-acetamidophenol, no biochemical alterations resembling those induced by 2-acetylaminofluorene were obtained, despite acute centrilobular necrosis of the livers. The findings point to a biochemical cascade beginning with administration of carcinogen and continuing through the development of hyperplastic nodules and of frank carcinomas resulting not from hepatotoxicity but as events associated with the hepatocarcinogenic progression.
D015073:2-Acetylaminofluorene; D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D019731:Carbon-Nitrogen Ligases; D004081:Dihydroorotate Oxidase / Q000378:metabolism; D008025:Ligases / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology*; D008115:Liver Regeneration; D008297:Male; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D011742:Pyrimidine Nucleotides / Q000096:biosynthesis*; D051381:Rats; D011916:Rats, Inbred F344; D013217:Starvation / Q000378:metabolism
D011742:Pyrimidine Nucleotides; D000082:Acetaminophen; D015073:2-Acetylaminofluorene; D004081:Dihydroorotate Oxidase; C029260:uridine diphosphate kinase; D009701:Nucleoside-Diphosphate Kinase; D008025:Ligases; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase