6-Fluoro-2-methylspiro(chroman-4,4'-imidazolidine)-2',5'-dione and related compounds as inducers of monooxygenase in rat liver microsomes.
The relationship between the structure of spirohydantoin derivatives and their inducing effects on hepatic monooxygenase system was studied. At the dose of 1 mumol/kg (0.3 mg/kg), 6-fluoro-2-methylspiro(chroman-4,4'-imidazolidine)-2',5'-dione (M79175) was found to exhibit an inducing effect on benzphetamine N-demethylase. On the contrary, the inducing effect of Sorbinil, in which the 2-methyl group on the chroman ring of M79175 was replaced by hydrogen atom, on benzphetamine N-demethylase was 100 times less than that of M79175. The substitution of the methyl group of M79175 with the dimethyl group did not affect the inducing effect, whereas the substitution with the hexyl group resulted in the loss of the inducing effect on drug oxidation activities tested at a dose of 10 mg/kg. Furthermore, cyclohexane spiro-2,6-chloro-1'-(3-dimethylaminopropyl)spiro(chroman-4,4'-imidazolid ine)-2' , 5'-dione (M79193) had an inducing effect on total cytochrome P-450 content, but had no inducing effect on benzphetamine N-demethylase. In addition, M79175 was found to induce cytochrome P-450 which is immunochemically related to one of the major forms of phenobarbital-inducible cytochrome P-450 (P-450(PB-1], but not cytochrome P-450 which is immunochemically related to the major form of 3-methylcholanthrene-inducible cytochrome P-450 (P-450(MC-1]. On the other hand, M79193 was found to induce neither P-450(PB-1) nor P-450(MC-1).
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D048289:Imidazolidines; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010089:Oxidoreductases, N-Demethylating / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D007093:Imidazoles; D048289:Imidazolidines; C037070:M 79175; D003577:Cytochrome P-450 Enzyme System; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating