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`Journal of Neurochemislry
`Raven Press, New York
`© 1982 International Society for Neurochemistry
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`This material may be protected by Copyright law (Title 17 US. Code)
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`0022-3042/82/0301-0848/$02.75/[)
`
`Short Communication
`
`Effects of Anticonvulsants on the Formation of
`3/—Hydroxybutyrate from 3/—Aminobutyrate in Rat Brain
`
`Susan R. Whittle and Anthony J. Turner
`
`Department 0fBiochemistry, Urtiversity of Leeds, Leeds, U.K.
`
`Abstract: The conversion of yaminobutyrate (GABA) via succinic semial—
`dehyde to 3/-hydroxybutyrate has been examined in rat brain homogenates. A
`number of anticonvulsants, including sodium valproate and phenobarbitone,
`inhibited this metabolic pathway. These results are interpreted in the light of
`the characteristics of aldehyde reductases known to reduce succinic semial-
`dehyde. Key Words: Aldehyde reductase—Anticonvulsants—Sodium
`valproate—y—Hydroxybutyrate—GABA metabolism—Succinic semialdehyde.
`Whittle S. R. and Turner A. J. Effects of anticonvulsants on the formation of
`y—hydroxybutyrate from y-aminobutyrate in rat brain. J. Neurochem. 38,
`848—851 (1982).
`
`Much attention has focussed on a role for y-
`aminobutyrate (GABA) in the control of epileptic convul-
`sions (Meldrum, 1975; Turner and Whittle, 1980). A dis-
`ruption of metabolism that causes a fall in the synaptic
`concentration of GABA could lead to a decrease in
`neuronal inhibition resulting in seizures. Alternatively,
`the concentration of GABA may be normal but its post-
`synaptic action could be impaired. Anticonvulsants might
`restore the inhibitory response to normal by acting at
`either of these two levels. It has been known for some
`years that the anticonvulsant sodium valproate (Epilim‘3 ,
`2—propylpentanoate) inhibits the conversion of GABA to
`its major metabolite, succinate (Harvey et al., 1975;
`Sawaya et al., 1975). However, it appears unlikely that
`this inhibition would be effective at normal clinical doses
`of the drug (Whittle and Turner, 1978; Turner and Whit-
`tle, 1980; Kerwin and Taberner, 1981). An alternative
`route of metabolism of GABA involves its transamination
`to succinic semialdehyde followed by reduction to y-
`hydroxybutyrate. This compound is apparently capable
`of inducing an epileptic-like state in animals (Marcus et
`al., 1967; Snead et al., 1976). Thus alterations in brain
`levels of y-hydroxybutyrate may affect the seizure
`threshold and are a potential site of action for valproate
`and similar compounds (Turner and Whittle, 1980; Ker-
`win and Taberner, 1981).
`The enzyme(s) responsible for the reduction of succinic
`
`Received July 30, 1981; accepted September 25, 1981.
`Address correspondence and reprint requests to D_r. A. .1.
`Turner, Department of Biochemistry, University of ‘Leeds, 9
`Hydc Terrace, Leeds LS2 9LS, U.K.
`
`848
`
`semialdehyde to y-hydroxybutyrate may be related to the
`family of NADPH—dependent aldehyde reductases (al-
`cohol:NADP‘ oxidoreductase, EC 1.1.1.2) (Kaufman et
`al., 1979). The major form of this enzyme has been shown
`to be very sensitive to inhibition by valproate, barbitu-
`rates, and some other anticonvulsants (Erwin and Die-
`trich, 1973; Whittle and Turner, 1978; 1981a,b; J avors and
`Erwin, 1980). Recently, however, a distinct reductase ex-
`hibiting high specificity and affinity for succinic semial-
`dehyde has been reported to occur in brain (Cash et al.,
`1979; Hoffmann et al., 1980; Rumigny et al., 1980; Rivvett
`et al., 1981). This latter enzyme is apparently insensitive
`to inhibition by anticonvulsants (Cash et al., 1979;
`Rumigny et al., 1980). The relative contribution of each of
`these reductases to the physiological production 01:7‘
`hydroxybutyrate from GABA has not been directly BS‘
`sessed. Clarification of the problem should reveal
`whether modifications in this metabolic pathway are rele-
`vant to the molecular actions of certain classes of
`anticonvulsants, as suggested elsewhere.
`_
`_
`The concentration of succinic semialdehyde in brain IS
`normally very low (approximately 104° mol/g brain‘
`Matsuda and Hoshino, 1977). Several authors have them?-
`fore argued that the specific and ‘high—affinity’ Suflclmc
`semialdehyde reductase would be the principal,
`If not
`exclusive, enzyme involved in 'y-hydroxybutyrate forma-
`tion from GABA (Hoffmann et al., 1980; Rumlgny at
`
`Abbreviation used: GABA, y»Aminobutyric acid.
`
`Page 3 of 6
`
`Page 3 of 6
`
`

`
`
`
`
`
`ANTICONVULSANTS AND 3/-AMINOBUTYRATE METABOLISM
`
`849
`
`al., 1981; Rivett et al., 1981). However, Anderson et al.
`' (1977) have shown that barbiturates markedly inhibit y-
`hydroxybutyrate formation in vitro, suggesting a signifi-
`cant role for the major aldehyde reductase in this process.
`These authors, though, used millimolar concentrations of
`succinic semialdehyde as substrate. To obtain a more
`realistic assessment of the rates of synthesis of y-
`hydroxybutyrate, we examined the effects of anticom-
`vulsants, valproate analogues, and other known aldehyde
`‘ reductase inhibitors on the overall formation of y—hydr0xy-
`butyrate from GABA in rat brain homogenates. Studies
`of this type have previously allowed us to assess the
`relative contribution of aldehyde reductase isoenzymes
`to the reductive metabolism of catecholamines (Whittle
`and Turner, 19810).
`
`MATERIALS AND METHODS
`
`Sodium valproate was a gift from Dr. D. S. Walter,
`Reckitt & Colman Pharmaceutical Division, Hull. The
`flavonoid inhibitors quercetin and quercitrin were ob-
`tained respectively from Sigma Chemical Corp. and from
`1.C.N. Pharmaceuticals Inc., Piscataway, New Jersey,
`U.S.A. 3/—Valerolactone was from Aldrich Chemical Co.,
`Gillingham, U.K. GABA aminotransferase (4—amino—
`butyrate:2—oxoglutarate aminotransferase, EC 2.6.1.19)
`was purified from rat brain and assayed as described pre-
`viously (Whittle and Turner, 1978).
`Brains obtained from male Wistar rats (170~190 g)
`were homogenised in 1 volume of 0.1 M—sodium phos-
`phate buffer, pH 7.0, and a sample (equivalent to 10 mg
`brain) was incubated at 37°C for 5 min in the presence of
`V GABA (1 mM), 2—oxoglutarate (1 mM) and NADPH (0.1
`mM). The reaction was terminated by the addition of 2 ml
`of trichloroacetic acid (50%, w/v). Denatured protein was
`removed by centrifugation and the supernatant was
`lyophilised. The residue was redissolved in 0.1 M—sodium
`
`phosphate buffer, pH 7 (1 ml), and heated at 90°C for 10
`min to convert the acid to a lactone derivative. After
`cooling on ice, the sample was adjusted to pH 6 and "y-
`valerolactone (2 pug) was added as internal standard. The
`sample was then extracted twice with 2 volumes of chlo-
`roform, and the pooled chloroform extracts were evapo-
`rated to approximately 100 Ml before samples were quan-
`titated by gas—liquid chromatography. The production of
`3/—hydroxybutyrate was linear with respect to time and
`protein concentration in the range tested. The recovery of
`product, determined by adding a known amount of y-
`hydroxybutyrate to the brain homogenate followed by the
`normal extraction procedure, was 85 : 5%.
`
`RESULTS
`
`The uninhibited reaction produced 0.107 : 0.018 p.g
`3/—hydroxybutyrate/min/g brain (wet weight) in the pres-
`ence of NADPH. The reaction rate in the presence of
`added coenzyme was threefold that observed in its ab-
`sence. NADH, however, produced no significant stimu-
`lation of reaction rate suggesting that the formation of
`3/—hydroxybutyrate from GABA is primarily NADPH-
`dependent. These data would be consistent with the re-
`port by Cash et al. (1979) that brain aldehyde reductases
`using succinic semialdehyde as substrate are NADPH-
`dependent.
`The effects of a range of anticonvulsants and aldehyde
`reductase inhibitors on 'y-hydroxybutyrate formation are
`listed in Table 1. Sodium valproate and its structural
`analogues, as well as phenobarbitone, all inhibited the
`reaction. The aldehyde reductase inhibitors quercetin and
`quercitrin also exerted significant inhibitory effects. The
`overall conversion of GABA to y—hydroxybutyrate in-
`volves the action of GABA aminotransferase (EC
`2.6.1.19) as well as aldehyde reductases. Thus, the effects
`of those compounds that inhibited y—hydroxybutyrate
`
`TABLE 1. Eflects of anticonvulsants and valproate analogues on
`3/—hydr0xybutyrate formation from GABA
`
`Drug
`(1 mM)
`
`None
`Anticonvulsants
`Sodium valproate
`Phenobarbitone
`Diphenylhydantoin
`Carbarnazcpine
`Phenacemide
`Valproate analogues
`Diphenylacetate
`2-Phenylbutyrate
`2—Ethylhexa11oate
`Other aldehyde reductase inhibitors
`Quercetin
`Quercitrin
`
`3/-Hydroxybutyrate formed
`(,ug/min/g brain)
`0.107 : 0.018 (9)
`
`Inhibition
`(%)
`-—
`
`0.035 1 0.002 (4)
`0.040 t 0.008 (4)
`0.088 1 0.021 (4)
`0.095 i 0.01 (4)
`0.080 1 0.011 (4)
`
`0.038 : 0.003 (4)
`0.041 : 0.003 (4)
`0.042 t 0.003 (4)
`
`0.029 : 0.009 (4)
`0.048 : 0.014 (4)
`
`67.3
`62.6
`17.8
`11.3
`25.2
`
`64.5
`61.7
`60.7
`
`72.9
`55.1
`
`Samples (1 pol) obtained as described in the text were injected into a Varian Aerograph
`1520 gas-liquid chromatograph containing a glass column (2 m X 3 mm i.d.) packed with
`6% diethyleneglycol—succinate on 100-120 mesh Phasesep NI DCMS, and connected to a
`flame—ionization detector. The temperature settings were 167°C, 128°C and 150°C for inlet,
`column and detector, respectively, and carrier gas (helium) flow rate was 35 ml/min. Re-
`tention times were 2.6 min for y-valerolactone and 1.7 min for y—hydroxybutyrate.
`Results are means :’s.D. for the numbers of animals indicated in parentheses.
`
`-,,_,_,_.
`
`Page 4 of 6
`
`J. Neurochem., Vol. 38, No. 3, 1982
`
`Page 4 of 6
`
`

`
`850
`
`S. R. WHITTLE AND A. J. TURNER
`
`TABLE 2. Efjfects of inhibitors of N/—hydr0xybm‘yrate
`for/mztion on the activity of GABA aminotransferase
`Rate
`Inhibition
`(nmol/min/ml)
`(%)
`6.1 1
`—
`5 .6
`8.4
`5 .88
`3.8
`5 .95
`2.6
`5 .63
`7.9
`5.80
`5.1
`5.95
`2.1
`5 .3
`13 .2
`
`Inhibitor
`None
`Sodium valproate
`Phenobarbitone
`Diphenylacetate
`2—Pheny1butyrate
`2-Ethylhexanoate
`Quercetin
`Quercitrin
`
`Rat brain GABA aminotransferase was purified and assayed
`as described for the enzyme from ox brain (Whittle and Turner,
`1978). All inhibitors were maintained at 1 mM.
`
`formation were also examined on the activity of the trans-
`aminase. None of the observed inhibitors of y-
`hydroxybutyrate formation had a significant effect on the
`activity of purified GABA aminotransferase at the con-
`centrations used in these studies (Table 2).
`
`DISCUSSION
`
`The present results suggest that the specific succinic
`semialdehyde reductase is not exclusively responsible for
`y-hydroxybutyrate formation from GABA under the con-
`ditions used here, since this enzyme is reported to be
`unaffected by barbiturates and sodium valproate (Cash et
`al., 1979; Rumigny et al., 1980). It would appear that the
`nonspecific (anticonvulsant—sensitive) aldehyde reductase
`may also contribute to a significant extent to this meta-
`bolic pathway. These conclusions would not be inconsis-
`tent with the established data on the two reductases
`purified from rat brain. If it is assumed that the intracel-
`lular (noninulin) space in brain is 0.56 ml/g tissue (see eg.
`Turner and Hick, 1975), then a value of approximately 1.8
`X 10” M is obtained for normal intracellular concentra-
`tions of succinic semialdehyde (Matsuda and Hoshino,
`1977). The specific reductase contributes 10-20% toward
`the total reductase activity in brain and both enzymes are
`cytosolic in location (Rumigny et al., 1980; 1981). The
`respective Michaelis constants for succinic semialdehyde
`are reported to be 28 ,u.M (specific reductase) and 140 um
`(nonspecific reductase), obtained with the purified en-
`zymes from rat brain (Rumigny et al., 1980). Given these
`parameters, the nonspecific reductase would be expected
`to contribute more than 50% of the total activity toward
`succinic semialdehyde reduction at physiological con-
`centrations of this substrate. Even at substantially lower
`concentrations of succinic semialdehyde, the nonspecific
`reductase would still make a significant contribution to-
`wards y—hydroxybutyrate production, in agreement with
`our data (Table 1). We cannot at present, though, rule out
`the possibility that the specific succinic semialdehyde re-
`, ductase may be localized in GABA—containing neurons.
`Relatively high concentrations of sodium valproate
`compared with those in clinical use (Sawaya et al., 1975)
`are required to cause significant
`inhibition of y-
`hydroxybutyrate formation (Table 1). Thus, it seems un-
`likely that valproate exerts its anticonvulsant effects
`through an action on this metabolic pathway. An alterna-
`tive mode of action of valproate must therefore be postu-
`
`J. Neurachem., Vol. 38, No. 3, 1982
`
`Page 5 of 6
`
`lated. An effect of valproate on the postsynaptic mem.
`brane is an attractive proposition in view of recent neuro.
`physiological studies suggesting that valproate augments
`the postsynaptic inhibitory effects of GABA (MacDonald
`and Bergey, 1979; Kerwin et al., 1980).
`
`Acknowledgments: S.R.W. is Emma and Leslie Reid
`Fellow of the University of Leeds. This work was sup.
`ported in part by the Medical Research Council.
`
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`
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