EFFECT OF SKF-525A ON LIVER-METABOLISM AND HEPATOTOXICITY OF TRIBUTYLTIN AND DIBUTYLTIN COMPOUNDS IN MICE

The effect of pretreatment with SKF-525A, which inhibits hepatic cytoc hrome P450 enzymes, on metabolism and hepatotoxicity was examined in m ice orally administered tributyltin chloride (TBTC) or dibutyltin dich loride (DBTC) at a dose of 180 mu mol/kcg. Analysis of butyltin compou nds showed that the main metabolites in liver of mice treated with TBT C alone were DBTC (40%) and dibutyl(3 -carboxylpropyl)tin chloride (TC OOH; 12-26%), with the levels of other butyltin compounds including TB TC comprising < 12% of total butyltin compounds at 3-24 h following tr eatment. The pretreatment with SKF-525A resulted in four- to tenfold i ncreased TBTC levels and a significant decrease of debutylated metabol ites, particularly DBTC (60 and 37% decrease) at both 3 and 6 h in liv er of mice treated with TBTC, leading to complete inhibition of hepato toxicity at 24 h. At 24 h after TBTC treatment, hepatic levels of TBTC and most of the debutylated metabolites in mice pretreated with SKF-5 25A did not differ significantly when compared to those in unpretreate d 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 hepat otoxicity were unaffected by pretreatment with SKF-525A. These results suggest that debutylated metabolites, in particular DBTC, are the mai n metabolites of butyltin compounds responsible for the induction of h epatotoxicity following in vivo administration of TBTC. The results al so indicate that cytochrome P450 enzymes may play a greater role in th e metabolism of TBTC to form DBTC or butyltin trichloride (MBTC) than that of DBTC to form MBTC in liver of mice.