Relationship between genomic DNA ploidy and parameters of liver damage during necrosis and regeneration induced by thioacetamide.
Thioacetamide proved to be a potent necrogenic agent when a single dose of 6.6 mmol/kg was administered intraperitoneally to rats. Its necrogenic ability was assessed on the basis of morphological and biochemical changes. The injury of centrilobular hepatocytes showed a peak of cell death 24 hr after thioacetamide administration; it was followed immediately by the regenerative response. Parallel increases of serum aminotransferases, isocitrate dehydrogenase and gamma-glutamyl transferase activities were observed. Severe liver damage was also evident at 24 hr on the basis of glutathione depletion (29% of control), malondialdehyde production (169%), cytochrome P-450 level decrease (26%) and increased activity of glutathione S-transferase (160%). We checked the regenerative response by determining nuclear DNA content in isolated hepatocytes 0, 6, 12, 18, 24, 36, 48 and 72 hr after thioacetamide administration. Changes in DNA cell distribution between G0-G1, S and G2 + M phases of the cell cycle were observed. The sharp decrease in the percentage of the tetraploid cell population (G2 + M phases) and the abrupt increase of the S-phase cells at 36 and 48 hr suggest transition from adult to fetal in hepatocyte populations obtained 24 and 36 hr after thioacetamide treatment. At 72 hr of treatment, hepatocyte populations showed recovery to adult state. In the shift from the adult to fetal, registered at 24, 36 and 48 hr after thioacetamide administration, mitosis seemed to precede the synthesis of DNA.
Díez-Fernández
C
C
Instituto de Bioquímica (C.S.I.C.) Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Boscá
L
L
Fernández-Simón
L
L
Alvarez
A
A
Cascales
M
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009336:Necrosis; D011003:Ploidies; D011123:Polyploidy; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000009:adverse effects*
D013853:Thioacetamide; D008315:Malondialdehyde; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D005982:Glutathione Transferase; D005978:Glutathione