The effect of estrogen (17β-estradiol; E2) replacement on the liver function was examined in ovariectomized rats. Ovariectomy decreased serum transaminase activity and physiological dosage levels of E2 replacement returned the activity up to or above non-ovariectomized levels. Under the conditions of this experiment the elevated serum transaminase levels in the E2 replacement were not coincident with histological changes suggestive of liver dysfunction. The elevations of both serum glutamic oxaloacetic transaminase (GOT) and serum mitochondrial GOT were accompanied by increased hepatic tissue activity, suggesting that the elevated serum levels can be attributed to the accelerated synthesis of the enzymes. On the other hand, the elevation of serum glutamic pyruvic transaminase was not accompanied by increased tissue activity in the original organs, namely liver, kidney, heart and skeletal muscle. Ovariectomy decreased serum albumin and inhibited development of rough endoplasmic reticulum in the liver, and E2 replacement returned them up to or above the non-ovariectomized levels.
To study the nephrotoxicity of carboplatin (cis-diammine-1, 1-cyclobutane dicarboxylate platinum II, CBDCA), an analogue of cisplatin, we examined its pharmacokinetics and functional and histopathological changes of the kidney in rats that received i.v. injection of carboplatin. Platinum concentrations in the whole plasma rapidly decreased during the first 2 hours and was undetectable at 72 hours following the carboplatin administration. Approximately 90% of the platinum in the whole plasma was ultrafilterable during the first 30 minutes. The renal tissue concentrations of platinum rapidly decayed during the first 4 hours and then slowly declined up to 120 hours following the carboplatin administration. Platinum concentrations in the renal cortex showed higher levels than those in the renal medulla throughout the experimental period. BUN levels were within the normal range except on day 7. Serum creatinine levels remained stable and normal during the 7 days. Histopathological alterations of the renal tubules were not observed during the experimental period. These results suggest that carboplatin has less nephrotoxicity than cisplatin, because of its rapid excretion through glomerulus and less accumulation in the tubular cells.
Structure-activity relationships and in vitro evaluation of eye irritation potential of salicylates in rabbits were studied. The primary eye irritation potential of ten salicylates was evaluated according to Draize method. The effects of chemicals on model protein and lipid were investigated in vitro. The effects of chemicals on the protein could be detected by the production of aggregates of human serum γ-globulin (HSG) and a good correlation was obtained between the ability of salicylates to produce aggregation of HSG and the potential of corneal irritation. The effects on the lipid could be detected by the adhesion potential of chemicals on lipid membrane and a linear correlation was not obtained between the adhesionary effects of salicylates on lipid membrane and the potential eye irritation. The corneal irritation and protein aggregation potencial of salicylates were correlated with the acid dissociation constant more closely than octanol/water partition coefficient. The destruction of a-helix of proteins in corneal surface by salicylates were observed from the nondestructive structural analysis of corneal surface by Fourier Transform (FT)-IR spectroscopy. These results suggest that eye irritation caused by salicylates are mainly the results of denaturation of proteins in ocular tissue and that the effects on protein depend on the dissociation potential of molecules.
Rat red blood cells were used as an in vitro method to evaluate the eye irritation potential of chemicals in rabbits. The results using 116 chemicals of various categories including medicines, pesticides, detergents and solvents were analyzed for the prediction of possibility of eye irritation potentials. Eye irritation of chemicals was examined according to Draize method and chemicals were classified into three categories, (1) non or mild irritants, (2) moderate or severe irritants and (3) strong or corrosive irritants, based on the recovery of damages. The in vitro method consisted of two methods detecting the effects of chemicals mainly on protein and lipid in the membrane, which were evaluated by the induction of methemoglobin and hemolysis, respectively. Non- or mild irritants induced neither methemoglobin formation nor hemolysis. Most of moderate or severe irritants induced hemolysis, however, the potentials were low. Strong or corrosive irritants had high potentials for the induction of methemoglobin. The multivariate estimation by the above two in vitro data sets were 77.6% predictive of the in vivo classification.