Valproic acid desaturation

Rettie AE, Boberg M, Rettenmeier AW, et al. Cytochrome P-450-catalyzed desaturation of valproic acid in vitro. Species differences, induction effects, and mechanistic studies. J Biol Chem 1988 263(27) 13733-13738. 

Desaturation of alkyl groups. This novel reaction, which converts a saturated alkyl compound into a substituted alkene and is catalyzed by cytochromes P-450, has been described for the antiepileptic drug, valproic acid (VPA) (2-n-propyl-4-pentanoic acid) (Fig. 4.29). The mechanism proposed involves formation of a carbon-centered free radical, which may form either a hydroxy la ted product (alcohol) or dehydrogenate to the unsaturated compound. The cytochrome P-450-mediated metabolism yields 4-ene-VPA (2-n-propyl-4pentenoic acid), which is oxidized by the mitochondrial p-oxidation enzymes to 2,4-diene-VPA (2-n-propyl-2, 4-pentadienoic acid). This metabolite or its Co A ester irreversibly inhibits enzymes of the p-oxidation system, destroys cytochrome P-450, and may be involved in the hepatotoxicity of the drug. Further metabolism may occur to give 3-keto-4-ene-VPA (2-n-propyl-3-oxo-4-pentenoic acid), which inhibits the enzyme 3-ketoacyl-CoA thiolase, the terminal enzyme of the fatty acid oxidation system. 

Figure 4.29 Aliphatic desaturation of VPA. Abbreviation VPA, valproic acid.

Rettie, A. E., Sheffels, P. R., Korzekwa, K. R., Gonzalez, F. J., Philpot, R. M., Baillie, T. A. CYP4 isozyme specificity and the relationship between omega-hydroxylation and terminal desaturation of valproic acid. Biochemistry 1995, 34, 7889-7895. 

Cytochrome P450 enzymes catalyze dehydrogenation as well as oxygenation reactions, including the oxidation of saturated to unsaturated hydrocarbons, alcohols to carbonyl compounds, and amines to imines or other unsaturated products. The most extensively investigated of these reactions in terms of mechanism is the desaturation of valproic acid to 2-/i-propyl-4-pentenoic... 

The ratio of 4-hydroxy to A -desaturated metabolites depends on the P450 isoform and is larger for CYP2B1 (37 1) than for CYP4B1 (2 1) . The proportion of the olefin is much higher when the substrate is the A- - -unsaturated valproic acid, a result that is particularly consistent with a mechanism in which the electron is transferred to the ferryl oxygen before the hydrogen . The structural determinants that control whether hydroxylation or desaturation occurs are unknown, but if the Shaik formalism applies (see Chapter 2), it is probable that the desaturation reaction involves the quartet rather than doublet hydroxylation transition state. 

Fisher, M.B., S.J. Thompson, V Ribeiro, M.C. Lechner, and A.E. Rettie (1998). P450-catalyzed inchain desaturation of valproic acid Isoform selectivity and mechanism of formation of A -valproic acid generated by baculovirus-expressed CYP3A1. Arch. Biochem. Biophys. 356, 63-70. 

Carbon oxidation reactions nsnally result in the formation of alcohol products, but in some instances they produce desaturated metabolites. Early examples are provided by the P450-cata-lyzed oxidative A -desaturation of valproic acid [88,89], A -desaturation of testosterone [90], and A -desaturation of sterols [91, 92] (Fig. 4.11). Additional examples are provided by the desaturation of lovastatin [93], ezlopitant [94], and capsaicin [95] (Fig. 4.12). In all these examples, hydroxylation to give the normally expected alcohol product also is observed, which suggests that in these substrates desaturation diverges at some point from the normal substrate hydroxylation reaction. 

Fig. 4.11 The A" -desaturation of valproic acid (a), A -desaturation of testosterone (b), and A -desaturation of 24-meth-yl-eholesterol (c) eatalyzed by cytochrome P450 enzymes...

Fig. 4.13 Two limiting mechanisms for the desaturation the first hydrogen abstraction is followed by an electron of valproic acid are illustrated. In one, a second hydrogen transfer to the ferryl species, resulting in carbocation for-...

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