Effects of butyltin compounds on mitochondrial respiration and its relation to hepatotoxicity in mice and Guinea pigs.
Because the mechanisms responsible for the difference in toxicity between different experimental animal species remain unclear, the effects of tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) on mitochondrial respiration were compared among the livers of mice and guinea pigs in vitro and in vivo. Further, the levels of these butyltin compounds and their derivatives in the mitochondrial fractions of the hepatocytes were investigated in these animal species. Administration of TBTC and DBTC to mice resulted in the obvious elevation of serum enzymatic activities, as well as the inhibition of succinate-linked State 3 respiration in hepatic mitochondria at 24 h after administration. On the other hand, these metal compounds failed to induce such hepatotoxicity or to inhibit mitochondrial respiration in guinea pigs. There was no significant difference between mice and guinea pigs in the IC50 (metal concentration observed in 50% inhibition of mitochondrial respiration) of TBTC and DBTC against the succinate-linked State 3 respiration of hepatic mitochondria in vitro, although the mitochondrial respiration of succinate-linked State 3 was inhibited in the liver of mice treated with the metals in vivo. The levels of total butyltin compounds in the mitochondrial fractions of hepatocytes were higher in the mice than in the guinea pigs, and the main butyltin compound in the mitochondrial fractions was DBTC in both species at 24 h after TBTC or DBTC administration. The amount of sulfhydryl groups, which were capable of binding with DBTC, in mice hepatic mitochondria was twice as large as that in guinea pigs, and the affinity of DBTC for the isolated hepatic mitochondria was higher in mice than in guinea pigs in vitro. These results suggested that the induction of hepatotoxicity by TBTC and DBTC in vivo was closely associated with the depression of mitochondrial respiration and that the difference in susceptibility to the metal-induced mitochondrial damages between mice and guinea pigs might result from the high affinity of butyltin compounds, in particular DBTC, for hepatic mitochondria in mice containing higher levels of sulfhydryl groups, compared with guinea pigs.
Ueno
Shunji
S
Laboratory of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Towada-shi, Aomori 034-8628, Japan. ueno@vmas.kitasato-u.ac.jp
Kashimoto
Takashige
T
Susa
Nobuyuki
N
Shiota
Yutaka
Y
Okuda
Masayuki
M
Mutoh
Ken-Ichiro
K
Hoshi
Fumio
F
Watanabe
Kiyotaka
K
Tsuda
Shuji
S
Kawazoe
Sadahiro
S
Suzuki
Takashi
T
Sugiyama
Masayasu
M
D000284:Administration, Oral; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D004785:Environmental Pollutants / Q000633:toxicity*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000378:metabolism*; D009947:Organotin Compounds / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D011048:Polarography; D013045:Species Specificity; D013347:Subcellular Fractions / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000633:toxicity*
D004785:Environmental Pollutants; D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C011559:tributyltin; C020735:dibutyldichlorotin