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Cytochrome P-450—Catalyzed Formation of Δ4-VPA, a Toxic Metabolite of Valproic Acid
Abstract
Liver damage induced by the antiepileptic drug valproic acid (VPA) is believed to be mediated by an unsaturated metabolite of the drug, Δ 4-VPA. In studies of the biological origin of this hepatotoxic compound, it was found that liver microsomes from phenobarbital-treated rats catalyzed the desaturation of VPA to Δ 4-VPA. Indirect evidence suggested that cytochrome P-450 was the responsible enzyme, a conclusion that was verified by studies with a purified and reconstituted form of the hemoprotein, which catalyzed the oxidation of VPA to 4- and 5-hydroxyvalproic acid and to Δ 4-VPA. Desaturation of a nonactivated alkyl substituent represents a novel metabolic function of cytochrome P-450 and probably proceeds via the conversion of substrate to a transient free radical intermediate, which partitions between recombination (alcohol formation) and elimination (olefin production) pathways. These findings have broad implications with respect to the metabolic generation of olefins and may explain the increased hepatotoxic potential of VPA when it is administered in combination with potent enzyme-inducing anticonvulsants such as phenobarbital.
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Cited by
Stepan, A. F., Walker, D. P., Bauman, J., Price, D. A., Baillie, T. A., Kalgutkar, A. S., & Aleo, M. D. (2011) · Chemical Research in Toxicology · doi:10.1021/tx200168d · Cited by 698
Self-citationInhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity
Fromenty, B., & Pessayre, D. (1995) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(95)00012-6 · Cited by 665
Valproic Acid Toxicity: Overview and Management
Sztajnkrycer, M. D. (2002) · Journal of Toxicology: Clinical Toxicology · doi:10.1081/clt-120014645 · Cited by 286
Scott, S. A., Sangkuhl, K., Shuldiner, A. R., Hulot, J.-S., Thorn, C. F., Altman, R. B., & Klein, T. E. (2012) · Pharmacogenetics and Genomics · doi:10.1097/fpc.0b013e32834d4962 · Cited by 261
Inhibition of Cytochrome P450 Enzymes
Correia, M. A., & Hollenberg, P. F. (2015) · Cytochrome P450 · doi:10.1007/978-3-319-12108-6_5 · Cited by 257
Metadata
- Authors
- Rettie, A. E., Rettenmeier, A. W., Howald, W. N., & Baillie, T. A.
- Venue
- Science
- Published
- 1987-02-20
- Volume
- 235
- Issue
- 4791
- Pages
- 890-893
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2073141598
- Cited by
- 250
- References
- 0
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- closed
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- Rettie, A. E., Rettenmeier, A. W., Howald, W. N., & Baillie, T. A. (1987). Cytochrome P-450—Catalyzed Formation of Δ4-VPA, a Toxic Metabolite of Valproic Acid. Science. https://doi.org/10.1126/science.3101178
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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