Modulation of tryptophan hydroxylase activity in vitro by ethanol depends on biopterin cofactor concentration

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.