The effects of
cytochrome P-450 (CYP) induction by
phenobarbital (PB), CYP 2B, 2C, and 3A inducer in mammalians, on
triphenyltin metabolism and toxicity in hamsters were studied. A single dose of 50 mg/kg of
triphenyltin chloride was given by gavage to hamsters after pretreatment with or without PB for 3 days continuously at a daily dose of 80 mg/kg intraperitoneally (i.p.). Although the
triphenyltin produced marked but reversible
hyperglycemia and
hypertriglyceridemia in PB-untreated hamsters, the pretreatment of hamsters with PB, which increased levels of CYP, suppressed the diabetogenic effects compared with PB-untreated hamsters. Furthermore, we investigated whether the mitigation of
triphenyltin-induced diabetogenic toxicity by PB pretreatment is due to an alteration of
triphenyltin metabolism.
Triphenyltin and its metabolites in liver, kidneys, pancreas and brain were determined by gas chromatography periodically for 96 h after
triphenyltin administration in both groups of hamsters. The initial
triphenyltin levels in the tissues of PB-pretreated hamsters were about half of those in the tissues of PB-untreated hamsters and PB pretreatment accelerated metabolism of
triphenyltin at early stage in hamsters. We also examined the other CYP 1A and 2A inducers,
beta-naphthoflavone (B-NF) and
3-methylcholanthrene (MC). The PB pretreatment showed the strongest suppression of the toxicity at 24 h after the
triphenyltin intubation, compared with the effects of B-NF and MC. In addition, the maximum proportion of
diphenyltin to parent
triphenyltin in pancreas was observed in PB-treated hamsters. These findings suggest that the induction of CYP system
enzymes affects the metabolism and toxicity of
triphenyltin in hamsters. Especially, based on effects of PB and other CYP inducers, PB induction has a key role in suppressing the diabetogenic action of
triphenyltin, i.e. by decreasing
triphenyltin accumulation in the hamsters.