Mechanism-based inactivation of cytochrome P450 3A4 by L-754,394

Biochemistry
L K LightningW F Trager

Abstract

Mechanism-based inactivation of human liver P450 3A4 by L-754,394, a Merck compound synthesized as a potential HIV protease inhibitor, was investigated using recombinant P450 3A4. Enzyme inactivation was characterized by a small partition ratio (3.4 or 4.3 +/- 0.4), i.e., the total number of metabolic events undergone by the inhibitor divided by the number of enzyme inactivating events, lack of reversibility upon extensive dialysis, no decrease in the characteristic 450-nm species relative to control, and covalent modification of the apoprotein. The major and minor products formed during the inactivation of P450 3A4 were the monohydroxylated and the dihydrodiol metabolites of L-754,394, respectively. L-754,394 that had been adducted to P450 3A4 was hydrolyzed under the conditions used for SDS-PAGE, Ni(2+) affinity chromatography, and proteolytic digestion. In addition, the modification was not stable to the acidic conditions of HPLC separation and CNBr digestion. The labile nature of the peptide adduct and the nonstoichiometric binding of the inactivating species to P450 3A4 precluded the direct identification of a covalently modified amino acid residue or the peptide to which it was attached. However, Tricine SDS-PAGE in combi...Continue Reading

Citations

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N-(2-hydroxy-1-indanyl)-5-(2-(1,1-dimethylethylaminocarbonyl)-4-((furano(2,3-b)pyridin-5-yl)methyl)piperazin-1-yl)-4-hydroxy-2-phenylmethylpentanamide
CYP3A protein, human
Catalysis
Plasma Membrane
High Pressure Liquid Chromatography Procedure
In Silico
Cyanogen Bromide
Cytochrome P-450 Oxygenase
Physical Dialysis
Alkalescens-Dispar Group

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