| Autor: |
Lu, Ping, Alterman, Michail A., Chaurasia, Chandra S., Bambal, Ramesh B., Hanzlik, Robert P. |
| Zdroj: |
Archives of Biochemistry and Biophysics; January 1997, Vol. 337 Issue: 1 p1-7, 7p |
| Abstrakt: |
A series of ω-substituted fatty acids with potential heme-coordinating groups was synthesized as inhibitors of lauric acid ω-hydroxylation. The compounds were evaluated using liver microsomes from clofibrate (CF)-induced rats and an engineered expressed CYP4A1-derived fusion protein called f4A1. ω-Imidazolyl-decanoic acid (compound 11) and ω-aminolauric acid (compound 7) were potent Type II ligands and potent inhibitors of lauric acid ω-hydroxylation in both CF-microsomes and f4A1. Replacing their terminal amino or imidazolyl groups with other potential iron-binding groups such as ω-methylsulfinyl-, ω-cyano-, ω-azido-, or ω-formamido all greatly reduced their potency as inhibitors of ω-hydroxylation and their affinity for cytochrome P450 as measured byKsvalues. In CF-microsomes, inhibition of (ω-1)-hydroxylation of lauric acid by a homologous series of ω-imidazolyl-alkanoic acids varied only 2-fold but in the same incubations inhibition of ω-hydroxylation increased 22-fold upon going from C-8 to C-12. A similar dependence of binding affinity and inhibitory potency on chain length was also seen in the f4A1 system. In contrast, chain length had little effect on activity amongn-alkylamines orN-alkylimidazoles lacking a carboxyl or other polar functional group, suggesting that 7, 11, and related bifunctional compounds interact with CYP4A1 in CF-microsomes and with f4A1 in a specific bidentate fashion. Imidazoles containing phenyl, benzyl, or phenylethyl substituents at N-1 interact less strongly than relatedN-alkyl-imidazoles of similar carbon number and hydrophobicity, suggesting that the steric bulk and/or rigidity of the phenyl ring is not well accommodated in the active site. |
| Databáze: |
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