MODULATION OF TRYPTOPHAN-HYDROXYLASE ACTIVITY IN-VITRO BY ETHANOL DEPENDS ON BIOPTERIN COFACTOR CONCENTRATION

The mechanism of ethanol action at serotonergic neuronal systems in th e brain was investigated by examining the effects of alcohols on the a ctivity of tryptophan hydroxylase (TPH) in vitro using natural type of biopterin as cofactor. Alcohols inhibited the activity of TPH prepare d from rat brain in a noncompetitive manner with respect to both the b iopterin cofactor and the L-tryptophan substrate. The rank order of in hibitory potency of the tested alcohols was n-propanol > iso-propanol > ethanol > methanol. The kinetic study indicated that alcohols more p otently 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 similar to 5% Of control activity, because K-i 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 ethano l on serotonergic neuronal systems.