Effects of pretreatment with SKF-525A on triphenyltin metabolism and toxicity in mice.
The effects of cytochrome P-450 inhibition by alpha-phenyl-alpha-propylbenzeneacetic acid 2-[diethylamino]-ethyl ester hydrochloride (SKF-525A), which inhibits the activity of a number of cytochrome P-450s, on triphenyltin metabolism and toxicity in mice were studied. At 24 h after triphenyltin administration, the triphenyltin levels in the tissues of SKF-525A-pretreated mice were about three times of those in the tissues of SKF-525A-untreated mice and the ratio of metabolites to parent triphenyltin in the tissues of SKF-525A-pretreated mice was lower than those in the tissues of SKF-525A-untreated mice. These data indicate that the pretreatment of SKF-525A decelerated the triphenyltin metabolism and increased triphenyltin accumulation in the tissues of mice. Although triphenyltin did not affect plasma glucose levels of in the SKF-525A-untreated mice, the triphenyltin produced marked hyperglycemia in SKF-525A-pretreated mice. These results suggest that the inhibition of cytochrome P-450 system enzymes by SKF-525A affects the metabolism and toxicity of triphenyltin and has a key role in inducing the hyperglycemic action of triphenyltin, i.e. by increasing triphenyltin accumulation in the mice.
Ohhira
S
S
Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, 321-0293, Tochigi, Japan. s-ohhira@dokkyomed.ac.jp
Matsui
H
H
Watanabe
K
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001711:Biotransformation; D001786:Blood Glucose / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009947:Organotin Compounds / Q000493:pharmacokinetics* / Q000633:toxicity*; D011335:Proadifen / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D009947:Organotin Compounds; D014280:Triglycerides; D003577:Cytochrome P-450 Enzyme System; C030665:triphenyltin; D011335:Proadifen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase