Effect of SKF-525A on liver metabolism and hepatotoxicity of tri- and dibutyltin compounds in mice.
The effect of pretreatment with SKF-525A, which inhibits hepatic cytochrome P450 enzymes, on metabolism and hepatotoxicity was examined in mice orally administered tributyltin chloride (TBTC) or dibutyltin dichloride (DBTC) at a dose of 180 mumol/kg. Analysis of butyltin compounds showed that the main metabolites in liver of mice treated with TBTC alone were DBTC (40%) and dibutyl(3-carboxylpropyl)tin chloride (TCOOH; 12-26%), with the levels of other butyltin compounds including TBTC comprising < 12% of total butyltin compounds at 3-24 h following treatment. The pretreatment with SKF-525A resulted in four- to tenfold increased TBTC levels and a significant decrease of debutylated metabolites, particularly DBTC (60 and 37% decrease) at both 3 and 6 h in liver of mice treated with TBTC, leading to complete inhibition of hepatotoxicity at 24 h. At 24 h after TBTC treatment, hepatic levels of TBTC and most of the debutylated metabolites in mice pretreated with SKF-525A did not differ significantly when compared to those in unpretreated mice, resulting in the induction of hepatotoxicity at 48 h, although levels of TCOOH decreased even at 24 h. In the case of DBTC treatment, > 95% of the butyltin compounds were detected as DBTC in liver, and the levels of DBTC inside cells as well as the induction of DBTC hepatotoxicity were unaffected by pretreatment with SKF-525A. These results suggest that debutylated metabolites, in particular DBTC, are the main metabolites of butyltin compounds responsible for the induction of hepatotoxicity following in vivo administration of TBTC. The results also indicate that cytochrome P450 enzymes may play a greater role in the metabolism of TBTC to form DBTC or butyltin trichloride (MBTC) than that of DBTC to form MBTC in liver of mice.
Ueno
S
S
Department of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Aomori, Japan.
Suzuki
T
T
Susa
N
N
Furukawa
Y
Y
Sugiyama
M
M
D000818:Animals; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000473:pathology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009947:Organotin Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D009954:Ornithine Carbamoyltransferase / Q000378:metabolism; D011335:Proadifen / Q000494:pharmacology*; D014220:Trialkyltin Compounds / Q000493:pharmacokinetics / Q000633:toxicity*
D004791:Enzyme Inhibitors; D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C056189:di-n-butyltin; C011559:tributyltin; D011335:Proadifen; D009954:Ornithine Carbamoyltransferase; C020735:dibutyldichlorotin