Effects of pretreatment with cytochrome P-450 inducers, especially phenobarbital on triphenyltin metabolism and toxicity in hamsters.
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.
Ohhira
S
S
Department of Hygiene, Dokkyo University School of Medicine, Tochigi, Japan. s-ohhira@dokkyomed.ac.jp
Matsui
H
H
Watanabe
K
K
D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008647:Mesocricetus; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009947:Organotin Compounds / Q000378:metabolism* / Q000633:toxicity*; D010634:Phenobarbital / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D019324:beta-Naphthoflavone / Q000494:pharmacology
D001786:Blood Glucose; D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009947:Organotin Compounds; D014280:Triglycerides; D008748:Methylcholanthrene; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; C030665:triphenyltin; D001219:Aspartate Aminotransferases; D010634:Phenobarbital