VALPROIC ACID METABOLISM BY CYTOCHROME-P450 - A THEORETICAL-STUDY OF STEREOELECTRONIC MODULATORS OF PRODUCT DISTRIBUTION

Semiempirical, molecular mechanics, and molecular dynamics calculations have been performed to theoretically examine the metabolism of 2-n-propylpentanoic acid (valproic acid, VPA), a widely used therapeutic agent for the control of seizure disorders, by cytochrome P450. In particular, the stereospecificity and product distribution of the hydroxylated metabolites of VPA are predicted for the P450cam isozyme and compared to the experimental data from microsomal P450. Quantum mechanical results are consistent with hypothesized mechanisms for the formation of 2-n-propyl-4-pentenoic acid (4-ene-VPA), a hepatotoxic metabolite, by a P450-catalyzed dehydrogenation reaction. The current theoretical results suggest that differences in the binding sites between mammalian P450 isozymes and P450cam may modulate the product distribution via steric interactions with the substrate.