Role of cytochrome P450 in hepatotoxicity induced by di- and tributyltin compounds in mice.
The role of cytochrome P450 in the induction of hepatotoxicity by butyltin compounds such as tributyltin chloride (TBTC) and dibutyltin dichloride (DBTC) was investigated in vivo. The pretreatment of mice with SKF-525A, which decreased hepatic levels of cytochrome P450, suppressed TBTC-induced hepatotoxicity, as estimated by serum ornithine carbamyl transferase activity, whereas pretreatment with phenobarbital (PB), which increased the levels of cytochrome P450, enhanced the hepatotoxicity of TBTC. In the case of DBTC, PB pretreatment enhanced hepatotoxicity, while SKF-525A had no effect. Under these experimental conditions only PB pretreatment was found to increase hepatic levels of tin in mice treated with TBTC. These results suggest that hepatic metabolism of butyltin compounds by cytochrome P450 is more closely related to the induction of hepatotoxicity by TBTC than by DBTC. The active tin compounds formed during hepatic metabolism, which are responsible for induction of hepatotoxicity, will be discussed.
Ueno
S
S
Department of Veterinary Public Health, School of Veterinary Medicine and Animal Sciences, Kitasato University, Aomori, Japan.
Susa
N
N
Furukawa
Y
Y
Sugiyama
M
M
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009947:Organotin Compounds / Q000378:metabolism / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D014220:Trialkyltin Compounds / Q000378:metabolism / Q000633:toxicity*
D065607:Cytochrome P-450 Enzyme Inhibitors; D009947:Organotin Compounds; D014220:Trialkyltin Compounds; C056189:di-n-butyltin; C011559:tributyltin; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; C020735:dibutyldichlorotin; D010634:Phenobarbital