[Affinity modification of membrane-bound microsomal cytochrome P-450 with lipophilic analogs of substrates].
The following lipophilic spin-labeled cytochrome P-450 analogs were synthesized: 2-octyl-4-(3-iodine-2-oxopropylidene)-2,3,5,5-tetramethylimidaz olidine-1-oxyl (RIII), 2-nonyl-4-(3-iodine-2-oxopropylidene)-2,3,5,5-tetramethylimidaz olidine-1-oxyl (RIV), 2-hepta-decyl-4-(3-iodine-2-oxopropylidene)-2,3,5,5-tetramethyl imidazolidine-1- oxyl (RV). The distribution coefficients, k, in water--lipid and water--octanol systems as well as the theoretical estimates of k for these and previously synthesized analogs, i.e., 4-(3-iodine-2-oxo-propylidenyl)-2,2,3,5,5-pentamethylimidazolid ine-1-oxyl (RI) and 2-hexyl-4-(3-iodine-2-oxopropylidene)-2,3,5,5-tetramethylimidaz olidine- 1-oxyl (RII) were determined. It was shown that RIII and RIV bind as type I substrates to cytochrome P-450 from rat microsomes induced with phenobarbital or 3-methylcholanthrene as well as to those from control rats. Radicals RIII and RIV inhibit the oxidation of aniline, aminopyrine and benzphetamine. RIII-RV strongly inhibit the O-deethylation of 7-etoxyresorufin. The inhibitory activity of the radicals increases in the following order: RV less than RIV less than or equal to RI less than or equal to RIII less than RII. The experimental results suggest that the inhibitory properties are nonmonotonuesly related to the lipophility. The high lipophility of RIII and its strong inhibitory properties permit to render the latter to the class of inhibitors which can be transported by liposome membrane vehicles to the liver, inhibit the in vivo activity of the microsomal system and thus prolong the effects of drugs oxidized by cytochrome P-450.
Subkhankulova
T N
TN
Liakhovich
V V
VV
Vaĭner
L M
LM
Reznikov
V A
VA
D000345:Affinity Labels / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals; D007425:Intracellular Membranes / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010084:Oxidation-Reduction; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000345:Affinity Labels; D065607:Cytochrome P-450 Enzyme Inhibitors; D005609:Free Radicals; D003577:Cytochrome P-450 Enzyme System
Affinnaia modifikatsiia membranosviazannogo mikrosomal'nogo tsitokhroma P-450 lipofil'nymi analogami substratov.