Cytochrome P-450--catalyzed formation of delta 4-VPA, a toxic metabolite of valproic acid

Science ◽  
1987 ◽  
Vol 235 (4791) ◽  
pp. 890-893 ◽  
Author(s):  
A. Rettie ◽  
A. Rettenmeier ◽  
W. Howald ◽  
T. Baillie
Keyword(s):  
Valproic Acid ◽  
Toxic Metabolite ◽  
Cytochrome P 450

scholarly journals The High Incidence of Valproate Hepatotoxicity in Infants May Relate to Familial Metabolic Defects

1990 ◽  
Vol 17 (2) ◽  
pp. 145-148 ◽  
Author(s):  
R.E. Appleton ◽  
K. Farrell ◽  
D.A. Applegarth ◽  
J.E. Dimmick ◽  
L.T.K. Wong ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Fatty Acid ◽  
Developmental Delay ◽  
Hepatic Failure ◽  
Metabolic Disorders ◽  
Acid Oxidation ◽  
Toxic Metabolite ◽  
Metabolic Defects ◽  
Intractable Seizures ◽  
High Incidence

ABSTRACT:The incidence of fatal hepatic failure associated with valproic acid (VPA) therapy is highest in children under the age of three years, particularly in those with developmental delay. The pathogenesis of VPA hepatotoxicity is unclear but may relate to the accumulation of a toxic metabolite of VPA which impairs fatty-acid oxidation. We describe two unrelated infants with developmental delay who developed hepatic failure while receiving VPA. Siblings of both children subsequently developed hepatic steatosis and intractable seizures without being exposed to VPA. This suggests that that the two children who developed liver failure when receiving VPA may have had a familial metabolic disorder. Familial metabolic disorders may account partly for the higher incidence of fatal hepatotoxicity described in infants receiving VPA.

scholarly journals L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: A case report

2017 ◽  
Vol 45 (3) ◽  
pp. 1268-1272 ◽  
Author(s):  
Cecilia Maldonado ◽  
Natalia Guevara ◽  
Alicia Silveira ◽  
Pietro Fagiolino ◽  
Marta Vázquez
Keyword(s):  
Valproic Acid ◽  
Seizure Control ◽  
Urea Cycle ◽  
Therapeutic Option ◽  
Rare Condition ◽  
Ammonia Level ◽  
Toxic Metabolite ◽  
Carnitine Supplementation ◽  
Carnitine Level ◽  
Psychiatric Setting

Valproic acid is a broad-spectrum anticonvulsant that has also gained attention in the psychiatric setting. With respect to safety, valproic acid may induce a seemingly rare condition, hyperammonemia, which can induce a wide variety of symptoms ranging from irritability to coma. The proposed mechanism of hyperammonemia involves depletion of carnitine and overproduction of a toxic metabolite, 4-en-valproic acid, both of which impair the urea cycle and thus ammonia elimination. Carnitine is a commonly used antidote for acute intoxication of valproic acid, but is not a therapeutic option for management of chronic adults with adverse effects related to valproic acid. We herein report a case involving a woman with epilepsy who developed hyperammonemia after a change in her anticonvulsant therapy. She reported increased seizures and gastrointestinal disturbances. Her ammonia, valproic acid, 4-en-valproic acid, and carnitine levels were monitored. Her ammonia level was elevated and her carnitine level was at the inferior limit of the population range. She was supplemented with carnitine at 1 g/day. After 1 month, her ammonia level decreased, her carnitine level increased, and her seizures were better controlled. Carnitine supplementation was useful for reversal of her hyperammonemia, allowing her to continue valproic acid for seizure control.

scholarly journals Reversible Neonatal Cholestasis Following In Utero Exposure to Valproic Acid

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Douglas G Chang ◽  
Martin Stein ◽  
David Sine ◽  
David Yeung ◽  
Frank Mannino
Keyword(s):  
Valproic Acid ◽  
Animal Models ◽  
Ductus Arteriosus ◽  
Hip Dislocation ◽  
Postnatal Growth ◽  
Gamma Aminobutyric Acid ◽  
Developmental Defects ◽  
Blood Concentrations ◽  
Teratogenic Potential ◽  
Cytochrome P 450

Valproic acid (VPA) is a branched-chain carboxylic acid with broad anticonvulsant activity. Its spectrum of activity is thought to be mediated by combined molecular effects on intercellular Na+ currents, neuron K+ channels, and inhibition of gamma-aminobutyric acid (GABA) transaminase (1,2). VPA is metabolized in the liver by cytochrome P-450 oxidase. Hepatotoxicity related to valproate therapy has been reported in certain individuals and appears to be caused by the accumulation of toxic metabolites, which may include 4-en-valproate (3). The hepatotoxicity has been ascribed to an inherited or acquired deficiency in the cytochrome P-450 enzyme-dependent beta-oxidation pathway, and is inducible by other drugs such as phenobarbital or phenytoin (4). Fatal hepatic failure can result, with a disproportionately large number of such cases observed in patients less than two years old with neurologic abnormalities, severe seizures, and multiple anti-epileptic drug therapy (3,5,6,7). However, neonatal hepatic toxicity in humans coincident with intrauterine VPA exposure has rarely been reported (8,9,10); these cases were never reversible, andconfounding etiologic variables could not be excluded. In pregnancy, VPA readily crosses the placenta and accumulates with fetal blood concentrations greater than those in the mother (11). It is a known human teratogen primarily associated with neural tube developmental defects such as spina bifida. A specific "fetal valproate syndrome," marked by fetal growth deficiency, developmental delay, and an increased incidence of craniofacial, cardiovascular, and digital abnormalities, has also been reported (1,3,12,13,14). Furthermore, a dose-dependent relationship in the occurrence of major malformations and minor anomalies has been suggested (15). Major malformations reported include persistent patent ductus arteriosus, trigonocephaly, aplasia of the first ribs, dysplasia of the sternum, meningomyelocele, aplasia of the radius, and congenital hip dislocation. Minor malformations included brachycephaly, dysmorphic facial features, long thin fingers, and inverted or accessory nipples. The teratogenic potential is thought to be mediated by a secondary zinc deficiency induced by complexing with VPA (16), as well as by inhibition of microsomal epoxide hydrolase (17), which may enhance the teratogenic potential of concomitant anticonvulsant therapy. Numerous animal models have been developed for the study of VPA. VPA has been shown to have equal teratogenic potential as trimethadione in mice (18). Skeletal abnormalities, delayed parturition, and postnatal growth (5) have been reported in both mice and rats receiving VPA. In addition, Paulson and Paulson (19) noted defects of the palate, eyes, heart, and limb buds in animal models. Animal models for a VPA-associated cholestasis, however, are lacking.

Cytochrome P-4502E1: its physiological and pathological role

1997 ◽  
Vol 77 (2) ◽  
pp. 517-544 ◽  
Author(s):  
C. S. Lieber
Keyword(s):  
Posttranscriptional Regulation ◽  
Therapeutic Potential ◽  
Heavy Drinking ◽  
Ethanol Metabolism ◽  
Toxic Metabolite ◽  
Enhanced Production ◽  
Radical Production ◽  
Obesity And Diabetes ◽  
Cytochrome P 450

The role of the microsomal ethanol-oxidizing system (MEOS) in hepatic ethanol metabolism is reviewed, with focus on its constitutive, ethanol-inducible cytochrome P-4502E1 (2E1). The MEOS was purified and reconstituted using 2E1, phospholipids, and cytochrome P-450 reductase and shown to oxidize ethanol to acetaldehyde, mainly as a monooxygenase and secondarily via hydroxyl radicals, with transcriptional and posttranscriptional regulation. Polymorphism of 2E1 was recognized, and enzymology (including cofactors, role of lipids, inducers, and inhibitors) as well as cellular and tissue distribution were chartered. Physiological functions involve lipid metabolism and ketone utilization in starvation, obesity, and diabetes. The most significant role of 2E1 is its adaptive response to high blood ethanol levels with a corresponding acceleration of ethanol metabolism. The associated free radical production, however, contributes to liver injury in the alcoholic. Most importantly, 2E1 has a unique capacity to activate many xenobiotics (85 of which are listed) to hepatotoxic or carcinogenic products. Induction of 2E1 also results in enhanced production of acetaldehyde, a highly reactive and toxic metabolite. The proliferation of the endoplasmic reticulum associated with 2E1 induction is also accompanied by enhanced activity of other cytochrome P-450s, resulting in accelerated metabolism of, and tolerance to, other drugs, as well as increased degradation of retinol and its hepatic depletion. Some substrates and metabolites, however, are innocuous and may eventually be used as markers of heavy drinking. Recently discovered effective 2E1 inhibitors also have great therapeutic potential.

Curcumin affords protection against valproic acid induced teratogenicity by curtailing oxidative stress and inhibiting CYP2C9 activity

RSC Advances ◽  
2015 ◽  
Vol 5 (101) ◽  
pp. 82756-82764 ◽  
Author(s):  
Akhilesh Kumar ◽  
Hardik Chandasana ◽  
Rabi Sankar Bhatta ◽  
Nikunj Sethi ◽  
Sudhaker Yadav ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Valproic Acid ◽  
Toxic Metabolite ◽  
Dose Dependent ◽  
Cyp2c9 Activity

The toxic metabolite (E)-2,4-diene-VPA is involved in generation of oxidative stress subsequently contributing in induction of malformations and anomalies and that curcumin affords dose dependent amelioration of the anomalies exerted by VPA.

In vitro evaluation of a toxic metabolite of sulfadiazine

1985 ◽  
Vol 63 (11) ◽  
pp. 1370-1372 ◽  
Author(s):  
N. H. Shear ◽  
S. P. Spielberg
Keyword(s):  
Trypan Blue ◽  
Human Lymphocytes ◽  
Covalent Binding ◽  
Blue Dye ◽  
Toxic Metabolite ◽  
In Vitro Production ◽  
Vitro Production ◽  
Cytochrome P 450 ◽  
System Toxicity

We have demonstrated the in vitro production of a potentially toxic metabolite of sulfadiazine. Human lymphocytes were incubated with sulfadiazine and a murine hepatic microsomal drug metabolizing system. Toxicity to cells was assessed by trypan blue dye exclusion. Covalent binding of labelled sulfadiazine to microsomes also was studied. Sulfadiazine toxicity to cells was dependent on microsomes and NADPH. Binding and toxicity were decreased when microsomes were boiled or cytochrome P-450 inhibited, and by the addition of N-acetylcysteine or glutathione. The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione. Covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.

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