Chronic liver injury by thioacetamide and promotion of hepatic carcinogenesis.
To verify whether a mild, but prolonged liver injury by chemicals needing bioactivation causes both hepatic cirrhosis and the appearance of hepatocyte nodules and tumors (providing the liver has been exposed previously to initiating stimuli), diethylnitrosamine-initiated and uninitiated rats were administered thioacetamide at low dose (250 mg/l drinking water) for 6 months. Hepatocyte nodule incidence as well as changes in the drug-metabolizing system were followed at monthly intervals. In the uninitiated rats a micronodular liver cirrhosis slowly developed upon thioacetamide chronic administration; a few hepatocyte focal lesions of small size were seen from the 3rd month onward. By contrast in the diethylnitrosamine-initiated thioacetamide-treated rats the liver was macronodular because of the appearance and growth of many hepatocyte nodules; some hepatomas were also seen. During thioacetamide administration both uninitiated and diethylnitrosamine-initiated rats underwent a progressive decrease of the cytochrome P-450 liver content as well as of the activity of aminopyrine N-demethylase, ethoxycoumarin O-deethylase and ethoxyresorufin O-deethylase. On the other hand, most components of the phase II of the drug-metabolizing system were markedly enhanced. In conclusion, chronic administration of thioacetamide at low doses provided strong promoting stimuli for previously initiated hepatocytes.
Gervasi
P G
PG
Istituto di Mutagenesi e Differenziamento, C.N.R., Pisa, Italy.
Longo
V
V
Marzano
M
M
Saviozzi
M
M
Malvaldi
G
G
D000081:Acetamides; D000818:Animals; D002273:Carcinogens; D004052:Diethylnitrosamine; D008099:Liver / Q000187:drug effects*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013853:Thioacetamide; D013997:Time Factors
D000081:Acetamides; D002273:Carcinogens; D013853:Thioacetamide; D004052:Diethylnitrosamine