Enhancement of the dimethylnitrosamine acute effects in rat liver by prior treatment with triton WR-1339.

Prior administration of Triton WR-1339 (tyloxapol, an anionic surfactant) to noninbred Sprague-Dawley male rats significantly enhanced the intensity of the necrogenic effect of dimethylnitrosamine (DMN) on the liver. This phenomenon was established by determination of NADP+-linked isocitrate dehydrogenase activity in the plasma and by histologic procedures. This enhancing effect was not due to an increase in the levels of DMN that reached the liver, because the content of DMN in the livers of Triton WR-1339-treated or untreated animals at 1 or 3 hours was not significantly different. Triton WR-1339 administration had no effect on DMN liver metabolism to formaldehyde or CO2; in addition, the covalent binding of DMN metabolites to nucleic acids or proteins was not modified by pretreatment with Triton WR-1339. However, in vitro, high concentrations (1 mg/ml) of Triton WR-1339 decreased the intensity of these parameters. This effect disappeared when the concentration was lowered to 0.4 mg/ml. Results are compatible with the hypothesis that the potentiating effects of Triton WR-1339 on liver damage caused by DMN and other hepatotoxins were due to a modification of the response of liver cells to injury.

Modulation of galactosamine-induced liver injury by some amino acids or Triton WR1339.

Galactosamine administration to rats (600 mg/kg, i.p.) produces a severe liver necrosis at 24 h. Pretreatment with cystine, tryptophan or methionine (600 mg/kg, p.o., 30 min before the hepatotoxin) significantly prevents galactosamine-induced liver necrosis. Glutamic or aspartic acids, however, were not protective under a similar dosage regimen. The prior administration of Triton WR1339 (1 g/kg, i.v., 30 min before galactosamine) significantly enhanced the liver response to galactosamine-induced liver injury, whereas the administration of tyrosine resulted in death of the animals.

Studies on the mechanism of enhancement of carbon tetrachloride hepatotoxicity by Triton WR 1339.

Pretreatment of rats with Triton WR 1339 significantly enhanced the intensity of CC14-induced liver necrosis. Previous workers suggested that this effect might be due to enhancement by Triton WR 1339 of cellular degradative processes. This pretreatment, however, also enhanced the intensity of covalent binding of [14C]CC14 metabolites to microsomal protein at 3 or 6 h, but not 1 h after its administration. This effect is not due to changes of microsomal P-450 content or increased activity of mixed-function oxygenase-metabolizing drugs like pentobarbital. Pretreatment with Triton WR 1339 also partially increased CC14-induced peroxidation of microsomal lipids at 1, 3 or 6 h after administration of the hepatotoxin. Liver concentrations of CC14 in Triton WR 1339-treated rats were significantly higher at 3 or 6 h but not at 1, 10 or 24 after its i.p. administration. Triton WR 1339 treatment decreased the body temperature of the rats and further intensified the decrease produced by CC14. Results suggest that, in addition to possible effects of Triton WR 1339 administration on liver-cell degradative processes, there are other actions of this detergent on CC14 activation and lipid peroxidation which might play a role in the heightened response of the liver of CC14-induced injury.