2-n-Propyl-2 -pentenoic acid

Hauck, R.-S. and Nau, H. (1996) Asymmetric synthesis and enantioselective teratogenicity of 2-n-propyl-4-pentenoic acid (4-ene-VPA), an active metabolite of the anticonvulsant drug, valproic acid. Toxicol. Lett. 49 41-48. 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

Rettenmeier, A. W., Gordon, W. R, Prickett, K. S., Levy, R. H., Baillie, T. A. Biotransformation and pharmacokinetics in the rhesus monkey of 2-n-propyl-4-pentenoic acid, a toxic metabolite of valproic acid. Drug Metab. Dispos. 1986, 14, 454-464. 

Rettenmeier, A.W., W.P. Gordon, K.S. Prickett, R.H. Levy, J.S. Lockard, K.E. Thummel et al. (1986). Metabolic fate of valproic acid in the rhesus monkey. Formation of a toxic metabolite, 2-n-propyl-4-pentenoic acid. Drug Metab. Dispos. 14,443-453. 

Baillie, T.A. (1988) Metabolic activation of valproic acid and drug-mediated hepatotoxicity. Role of the terminal olefin 2-n-propyl-4-pentenoic acid. Chem. Res. Toxicol. 1 195-199. 

Bjorge SM, Baillie TA (1985) Inhibition of medium-chain fatty acid P-oxidation in vitro by valproic acid and its unsaturated metabolite, 2-n-propyl-4-pentenoic acid. Biochem Biophys Res Commun 132 245-252... 

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. 

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