SKF 525-A inhibition, induction, and 452-nm complex formation.
After administration of SKF 525-A to rats a portion of the cytochrome P-450 in hepatic microsomes was found in the reduced form as a stable complex absorbing at 452 nm. As much as 40% of the total cytochrome P-450 was bound in the complexed form after a single administration of SKF 525-A. The addition of potassium ferricyanide (50 muM) to hepatic microsomes from SKF 525-A-treated rats destroyed the complex and made the total cytochrome P-450 available for carbon monoxide binding. At early times after administration of SKF 525-A, when the amount of complexed cytochrome P-450 was maximum, mixed-function oxidase activities (p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation) were greatly inhibited. Later, as the amount of complexed cytochrome P-450 slowly decreased, these mixed-function oxidase activities gradually returned and reached control values in about 48 hr. Induction with daily doses of SKF 525-A for several days increased total cytochrome P-450 content up to 5-fold, which was more than induction with phenobarbital, but this was evident only after destruction of the complex with ferricyanide. The maximum increase in uncomplexed cytochrome P-450 was only 2-fold. Treatment of these microsomal suspensions with ferricyanide enhanced ethylmorphine N-demethylase, p-nitroanisole O-demethylase and norbenzphetamine 455-nm complex formation.
D000818:Animals; D001665:Binding Sites; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D009575:Nitroanisole O-Demethylase / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D013053:Spectrophotometry; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; D011335:Proadifen; D009575:Nitroanisole O-Demethylase; D005037:Ethylmorphine-N-Demethylase; D010634:Phenobarbital