Midazolam Oxidation by Cytochrome P450 3A4 and Active-Site Mutants: an Evaluation of Multiple Binding Sites and of the Metabolic Pathway That Leads to Enzyme Inactivation

• Published in: Molecular pharmacology Vol. 61; no. 3; pp. 495 - 506
• Main Authors: Khan, Kishore K, He, You Qun, Domanski, Tammy L, Halpert, James R
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.03.2002
• Subjects: Amino Acid Substitution; Anesthetics, Intravenous - metabolism; Anesthetics, Intravenous - pharmacology; Animals; Binding Sites; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Enzyme Inhibitors - pharmacology; Midazolam - metabolism; Midazolam - pharmacology; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - chemistry; Mixed Function Oxygenases - genetics; Mixed Function Oxygenases - metabolism; Models, Molecular; Mutation; Oxidation-Reduction; Rats; Statistics as Topic

Midazolam (MDZ) oxidation by recombinant CYP3A4 purified from Escherichia coli and 30 mutants generated at 15 different substrate recognition site positions has been studied to determine the role of individual residues in regioselectivity and to investigate the possible existence of multiple binding...