Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid

Porubek, David J.; Barnes, Hope; Meier, Gregor; Theodore, Louis; Baillie, Thomas A.

doi:10.1021/tx00007a006

Cited by 13 publications

(4 citation statements)

References 14 publications

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“…This reaction was investigated in detail for the desaturation of valproic acid to 2-propyl-4-pentenoic acid. [137][138][139][140][141] The introduction of a double bond into the valproic acid hydrocarbon terminus is readily rationalized by two mechanisms (Figure 16). Both of these mechanisms are initiated by hydrogen abstraction from the ω-1 carbon of valproic acid.…”

Section: Probes For Cationic Intermediatesmentioning

confidence: 99%

“…However, the evidence for a cation provided by this desaturation process is tainted by the fact that a mechanism can be formulated that only requires a radical intermediate. This reaction was investigated in detail for the desaturation of valproic acid to 2-propyl-4-pentenoic acid. − The introduction of a double bond into the valproic acid hydrocarbon terminus is readily rationalized by two mechanisms (Figure ). Both of these mechanisms are initiated by hydrogen abstraction from the ω-1 carbon of valproic acid.…”

Section: Oxygen Insertion Into the C−h Bondmentioning

confidence: 99%

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Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

2009

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Section: Probes For Cationic Intermediatesmentioning

confidence: 99%

Section: Oxygen Insertion Into the C−h Bondmentioning

confidence: 99%

Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

2009

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“…Desaturation has been experimentally observed for a number of P450 substrates including valproic acid, [54][55][56][57][58] ezlopitant, 59 sterols such as testosterone, 60 and long chain fatty acids, including lauric acid. 61 While two possible mechanisms may be devised for Cpd I-catalyzed desaturation, proceeding through either radical or carbocation intermediates, prior theoretical studies of trans-2-phenyl-iso-propylcyclopropane oxidation have suggested that a carbocation intermediate should dominate.…”

Section: Substrate Desaturationmentioning

confidence: 99%

Ab initio dynamics of the cytochrome P450 hydroxylation reaction

Elenewski

Hackett

2015

The Journal of Chemical Physics

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The iron(IV)-oxo porphyrin π-cation radical known as Compound I is the primary oxidant within the cytochromes P450, allowing these enzymes to affect the substrate hydroxylation. In the course of this reaction, a hydrogen atom is abstracted from the substrate to generate hydroxyiron(IV) porphyrin and a substrate-centered radical. The hydroxy radical then rebounds from the iron to the substrate, yielding the hydroxylated product. While Compound I has succumbed to theoretical and spectroscopic characterization, the associated hydroxyiron species is elusive as a consequence of its very short lifetime, for which there are no quantitative estimates. To ascertain the physical mechanism underlying substrate hydroxylation and probe this timescale, ab initio molecular dynamics simulations and free energy calculations are performed for a model of Compound I catalysis. Semiclassical estimates based on these calculations reveal the hydrogen atom abstraction step to be extremely fast, kinetically comparable to enzymes such as carbonic anhydrase. Using an ensemble of ab initio simulations, the resultant hydroxyiron species is found to have a similarly short lifetime, ranging between 300 fs and 3600 fs, putatively depending on the enzyme active site architecture. The addition of tunneling corrections to these rates suggests a strong contribution from nuclear quantum effects, which should accelerate every step of substrate hydroxylation by an order of magnitude. These observations have strong implications for the detection of individual hydroxylation intermediates during P450 catalysis. C 2015 AIP Publishing LLC. [http://dx

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“…Phenobarbital induces the formation of 4-en-VPA from VPA via the microsomal cytochrome P-450 system (25)(26)(27). Chronic cotreatment of young rats with VPA and phenobarbital doubled the plasma 4-en-VPA level and induced hepatic steatosis (7, 8).…”

mentioning

confidence: 99%

Reversal of the Adverse Chronic Effects of the Unsaturated Derivative of Valproic Acid—2-n-Propyl-4-Pentenoic Acid—on Ketogenesis and Liver Coenzyme A Metabolism by a Single Injection of Pantothenate, Carnitine, and Acetylcysteine in Developing Mice

Thurston

Hauhart

1993

Pediatr Res

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ABSTRACT. Like treatment with the parent compound unsaturated intermediates of VPA alkylate, and thereby cause valproic acid (VPA), acute and/or chronic treatment with irreversible inhibition of, key enzymes of /3-oxidation (10, 11). the unsaturated derivative, 2-n-propyl-4-pentenoic acid Gerber et al. (12) were among the first to report VPA-associ-(4-en-VPA), decreased ketogenesis and lowered free CoA, ated irreversible hepatic failure in young infants and children. acetyl CoA, and free carnitine levels in the livers of normal Because of the structural similarity of the unsaturated metabolite developing mice. Concomitantly, there were manifold in-of VPA, 4-en-VPA, to two well-known hepatotoxins-4-pentencreases in the content of medium-chain acyl CoA esters oic acid and toxic hypoglycin A metabolites (13, 14)-the authors (4-en-VPA CoA and 4-en-VPA CoA metabolites). Acute believed that 4-en-VPA played a major role in the pathogenesis cotreatment of 4-en-VPA-treated animals with pantoth-of VPA-induced hepatotoxicity. The present study is a test of enate, carnitine, and acetylcysteine caused significant ame-this hypothesis in normal developing mice. Its results appear to lioration of these metabolic aberrations. In animals chron-be applicable to an explanation of the mechanism of action of ically treated with 4-en-VPA, a single injection of panto-these other hepatotoxins. Because we have found that coadminthenate, carnitine, and acetylcysteine returned the istration of pantothenate and carnitine with VPA ameliorated its 4-en-VPA-depressed levels of P-hydroxybutyrate in adverse effects on ketogenesis and liver CoA metabolism (15), plasma and free CoA and acetyl CoA in liver to normal. effects of a similar regimen in acutely and chronically 4-en-VPAThese findings support the hypothesis that VPA-and treated mice were also examined. 4-en-VPA-induced hepatic dysfunction is produced by CoA sequestration rather than by irreversible inhibition by alkylation of the enzymes of fatty acid &oxidation by reactive MATERIALS AND METHODS intermediates. The findings also support the important but little-known role of carnitine in CoA metabolism-carniPantothenate (D-pantothenic acid, hemicalcium salt), and Ntine relieves the inhibition of pantothenate kinase, the rate-acetyl-L-cysteine were purchased from Sigma Chemical Co., St. controlling first enzyme in the pathway of CoA synthesis Louis, MO. Solutions of N-acetyl-L-cysteine were neutralized to by its product, free CoA, and by CoA esters. (Pediatr Res pH 7.0 with NaOH just before use. 4-en-VPA and sterile 0.9% 33: [72][73][74][75][76]1993) NaCl were gifts of Abbott Laboratories, Chicago, IL; L-carnitine was a gift of Sigma-Tau, Rome, Italy. Abbreviations and many others). Two acutely or chronically, were not significantly different; therefore, major mechanisms for this adverse action have been proposed. results were pooled. Other littermates received 4-en-VPA plus o n e relates to the depletion of free CoA in liver due to its pantothenate (vitamin B5; COA precursor), 2 mmol...

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Enantiotopic differentiation during the biotransformation of valproic acid to the hepatotoxic olefin 2-n-propyl-4-pentenoic acid

Cited by 13 publications

References 14 publications

Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

Hydrocarbon Hydroxylation by Cytochrome P450 Enzymes

Ab initio dynamics of the cytochrome P450 hydroxylation reaction

Reversal of the Adverse Chronic Effects of the Unsaturated Derivative of Valproic Acid—2-n-Propyl-4-Pentenoic Acid—on Ketogenesis and Liver Coenzyme A Metabolism by a Single Injection of Pantothenate, Carnitine, and Acetylcysteine in Developing Mice

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