Comparison of hepatotoxicity and metabolism of butyltin compounds in the liver of mice, rats and guinea pigs.
The hepatotoxicity of tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was compared among mice, rats and guinea pigs in vivo. Further, the metabolism of these butyltin compounds in the liver was also investigated in these species. The oral administration of TBTC and DBTC to mice induced obvious liver injury, as demonstrated by both serodiagnosis and histopathological diagnosis. The concentrations of TBTC and DBTC that induced hepatotoxicity in mice at 24 h after oral administration were 180 and 60 micro mol/kg, respectively. In the case of rats, the liver injury induced by TBTC and DBTC was detected at 24 h by the serodiagnosis, but not by histopathological diagnosis. On the other hand, in guinea pigs, TBTC and DBTC administration did not produce any clear liver injury at 24 h, as evaluated by these two diagnostic methods. Thus, the following ranking was obtained with regard to increasing order of sensitivity to liver injury caused by TBTC and DBTC: mice, rats and guinea pigs. The total butyltin contents in the liver of mice were equivalent at 3 h and 24 h after the administration of TBTC or DBTC; however, the contents in the liver of rats and guinea pigs were relatively lower at 3 h and higher at 24 h than those of mice, although there were no differences between rats and guinea pigs in the total liver butyltin content. Concerning the liver metabolism of these butyltin compounds, the main form of butyltin compounds in these animals treated with TBTC was DBTC within 3 h after oral administration, while the main metabolites at 24 h were different in each species, indicating that the liver metabolism of TBTC might vary by animal type. When the animals were treated with DBTC orally, DBTC was hardly metabolized in the livers of these animals even at 24 h, and the liver levels of DBTC were two times greater in mice and guinea pigs than in rats at 3 h and were lower in mice at 24 h than in rats and guinea pigs. The analysis of cellular distributions of DBTC in the liver at 3 h after the administration showed that the levels of DBTC in the nuclear, microsomal and mitochondrial fractions of mice hepatocytes were relatively higher than in those of rats, which were greater than in those of guinea pigs. These results suggest differences in the sensitivity of mice, rats and guinea pigs to hepatotoxicity caused by butyltin compounds and demonstrate that the difference in the sensitivity of these animals to the hepatotoxicity induced by TBTC and DBTC may be partly due to differences in hepatic metabolism of TBTC and in the distribution of DBTC within cell organelles, respectively.
Ueno
Shunji
S
Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Higashi 23-35-1, 034-8628 Towada-shi, Aomori, Japan. ueno@vmas.kitasato-u.ac.jp
Kashimoto
Takashige
T
Susa
Nobuyuki
N
Ishii
Masamitsu
M
Chiba
Toshikazu
T
Mutoh
Ken-ichiro
K
Hoshi
Fumio
F
Suzuki
Takashi
T
Sugiyama
Masayasu
M
D000284:Administration, Oral; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D009947:Organotin Compounds / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000378:metabolism / Q000633:toxicity*
D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C011559:tributyltin; C020735:dibutyldichlorotin