Cytochrome P-450-catalyzed desaturation of valproic acid in vitro. Species differences, induction effects, and mechanistic studies
The cytochrome P-450-mediated desaturation of valproic acid (VPA) to its hepatotoxic metabolite, 2-n-propyl-4-pentenoic acid (4-ene-VPA), was examined in liver microsomes from rats, mice, rabbits and humans. The highest substrate turnover was found with microsomes from rabbits (44.2 +/- 2.7 pmol of product/nmol P-450/15 min), while lower activities were observed in preparations from human, mouse, and rat liver, in that order. Pretreatment of animals with phenobarbital led to enhanced rates of formation of 4-ene-VPA in vitro and yielded induction ratios for desaturation ranging from 2.5 to 8.4, depending upon the species. Comparative studies in the rat showed that phenobarbital is a more potent inducer of olefin formation than either phenytoin or carbamazepine. The mechanism of the desaturation reaction was studied by inter- and intramolecular deuterium isotope effect experiments, which demonstrated that removal of a hydrogen atom from the subterminal C-4 position of VPA is rate limiting in the formation of both 4-ene- and 4-hydroxy-VPA. Hydroxylation at the neighboring C-5 position, on the other hand, was highly sensitive to deuterium substitution at that site, but not to deuteration at C-4. Based on these findings, it is proposed that 4-ene- and 4-hydroxy-VPA are products of a common P-450-dependent metabolic pathway, in which a carbon-centered free radical at C-4 serves as the key intermediate. 5-Hydroxy-VPA, in contrast, derives from an independent hydroxylation reaction.
- Research Organization:
- Univ. of Washington, Seattle (USA)
- OSTI ID:
- 6691443
- Journal Information:
- J. Biol. Chem.; (United States), Vol. 263:27
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CARBOXYLIC ACIDS
HYDROXYLATION
DEUTERIUM
ISOTOPE EFFECTS
BIOLOGICAL PATHWAYS
CYTOCHROMES
ENZYME INDUCTION
GENETIC VARIABILITY
IN VITRO
LIVER
MAN
METABOLISM
MICE
MICROSOMES
PHENOBARBITAL
PROTEINS
RABBITS
RATS
ANESTHETICS
ANIMALS
ANTICONVULSANTS
AZINES
BARBITURATES
BIOLOGICAL VARIABILITY
BODY
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM DEPRESSANTS
DIGESTIVE SYSTEM
DRUGS
GENE REGULATION
GLANDS
HETEROCYCLIC COMPOUNDS
HYDROGEN ISOTOPES
HYPNOTICS AND SEDATIVES
ISOTOPES
LIGHT NUCLEI
MAMMALS
NUCLEI
ODD-ODD NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
ORGANOIDS
ORGANS
PIGMENTS
PRIMATES
PYRIMIDINES
RODENTS
STABLE ISOTOPES
VERTEBRATES
550501* - Metabolism- Tracer Techniques