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Hexobarbital, a short-acting hypnotic, is metabolized to 3'-hydroxyhexobarbital by cytochrome P450, and then to 3'-oxohexobarbital by liver cytosolic dehydrogenase. New methods of separation for hexobarbital and its metabolites by TLC have been developed and applied to study the metabolism of hexobarbital enantiomers and stereoselective metabolism of hexobarbital. (+)-Hexobarbital preferentially was transformed into beta-3'-hydroxyhexobarbital and the (-)-enantiomer preferentially transformed into alpha-3'-hydroxyhexobarbital by rat liver microsomes. Glucuronidation and dehydrogenation of 3'-hydroxyhexobarbital were also stereoselective and the S-configuration at the 3'-position was preferred. Alpha-3'-hydroxyhexobarbital from (-)-hexobarbital and the beta-isomer from (+)-hexobarbital were shown to be preferentially conjugated with glucuronic acid in rabbit urine, and to be preferentially dehydrogenated to form 3'-oxohexobarbital by rabbit and guinea pig 3-hydroxyhexobarbital dehydrogenases. A new metabolic pathway of hexobarbital was found in which 3'-oxohexobarbital reacts with glutathione to form 1,5-dimethylbarbituric acid and a cyclohexenone-glutathione adduct, a novel metabolite. 1,5-dimethylbarbituric acid was excreted into the urine and the cyclohexenone-glutathione adduct into the bile of rats dosed with hexobarbital. 3-hydroxyhexobarbital dehydrogenases that dehydrogenate 3-hydroxyhexobarbital into 3'-oxohexobarbital were purified from the liver cytosol of rabbits, guinea pigs, goats, rats, mice, hamsters, and humans and characterized. These enzymes were monomeric proteins and had molecular weights of about 34500-42000, and used NAD(+) and NADP(+) as cofactors, except for the human enzyme that had a molecular weight of about 58000 and used NAD(+) alone. Each enzyme exhibited its own characteristics. Substrate specificity demonstrated that 3-hydroxyhexobarbital dehydrogenases dehydrogenate not only alpha,beta-unsaturated cyclic and acyclic secondary alcohols but also some 17 beta-, 3 alpha-hydroxysteroids or both, except for the human enzyme. The amino acid sequence of the hamster enzyme indicated that it belongs to the aldo-keto reductase superfamily and hydroxysteroid dehydrogenase subfamily.

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New Aspects of Hexobarbital Metabolism: Stereoselective Metabolism, New Metabolic Pathway via GSH Conjugation, and 3-Hydroxyhexobarbital Dehydrogenases