Matsubara K, Kobayashi Y, Tanabe Y, Maruyama W, Ishinaga Y, Idzu T, Kimura K, Naoi M
Legal Medicine Department, Shimane Medical University, Izumo, Japan.
Alcohol. 1996 Sep-Oct;13(5):455-9. doi: 10.1016/0741-8329(96)00033-x.
The mechanism of ethanol action at serotonergic neuronal systems in the brain was investigated by examining the effects of alcohols on the activity of tryptophan hydroxylase (TPH) in vitro using natural type of biopterin as cofactor. Alcohols inhibited the activity of TPH prepared from rat brain in a noncompetitive manner with respect to both the biopterin cofactor and the L-tryptophan substrate. The rank order of inhibitory potency of the tested alcohols was n-propanol > iso-propanol > ethanol > methanol. The kinetic study indicated that alcohols more potently affected the enzyme interaction with cofactor than substrate. Ethanol, at concentrations that can be reasonably attained in vivo (i.e., 25-100 mM) significantly decreased TPH activity in the presence of a physiological concentration of cofactor. However, the reduction was only approximately 5% of control activity, because Ki, values of ethanol for the enzyme were very high (800-1000 mM). From the present results, it was concluded that the direct inhibition of the synthetic enzyme itself by ethanol would contribute little to in vivo effects of ethanol on serotonergic neuronal systems.
通过使用天然型生物蝶呤作为辅因子，在体外检测醇类对色氨酸羟化酶（TPH）活性的影响，研究了大脑中乙醇在5-羟色胺能神经元系统的作用机制。醇类对从大鼠脑制备的TPH活性具有非竞争性抑制作用，这种抑制作用针对生物蝶呤辅因子和L-色氨酸底物两者。所测试醇类的抑制效力顺序为正丙醇>异丙醇>乙醇>甲醇。动力学研究表明，醇类对酶与辅因子相互作用的影响比对底物的影响更显著。在生理浓度辅因子存在下，体内能够合理达到的乙醇浓度（即25-100 mM）会显著降低TPH活性。然而，这种降低仅约为对照活性的5%，因为乙醇对该酶的Ki值非常高（800-1000 mM）。从目前的结果得出结论，乙醇对合成酶本身的直接抑制对乙醇在5-羟色胺能神经元系统的体内作用贡献不大。
