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The steady-state kinetics of tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating); EC 1.14.16.2] frequently exhibits complex features which confound interpretation of the results. Using an assay-enzyme system which is essentially devoid of the major mitigating kinetic features, a comprehensive kinetics data base has been compiled. The studies employed L-tyrosine, 5,6,7,8-tetrahydrobiopterin, and oxygen as substrates, and 3-(3',4'-dihydroxyphenyl)L-alanine, a deazapterin, 3-iodo-L-tyrosine, and dopamine as product, substrate analogue, and product analogue inhibitors, respectively. All three reactants were varied pairwise, and all inhibitors (except dopamine) were tested with each of the three substrates as variable substrate. The entire data base was interpreted exclusively in terms of models for classic saturation kinetics of enzyme catalysis, providing an internally consistent kinetic model and evidence for a sequential mechanism with partially ordered sequences for substrate addition and product release. Some possible mechanisms and experimental variables relating these results to more complex kinetics of tyrosine hydroxylase are considered briefly.

We have studied the regional and subcellular distribution, functional role, and pharmacology of quinoid dihydropterin reductase (QDPR) and endogenous reduced pterins (PH4) subserving tyrosin hydroxylase (TOH) and tryptophan hydroxylase in the rat brain. There is a significant correlation between the regional distribution of PH4 and TOH but not between PH4 and tryptophan hydroxylase or between either TOH or tryptophan hydroxylase and QDPR. This suggests that a major portion of PH4 is associated with the biosynthetic activity of brain catecholaminergic systems. The regional and subcellular distribution of QDPR was inconsistent with a regulatory function for QDPR in monoamine synthesis. In vitro measures of PH4, TOH, and synaptosomal dopamine (DA) and serotonin synthesis in the striate cortex of untreated animals and animals subjected to neurotoxin or electrolytic lesions of the dorsal raphe or substantia nigra exhibit significant covariation of PH4 with synaptosomal DA but not serotonin synthesis and a significant partial correlation of PH4 with DA synthesis. The subcellular distribution of PH4 in the striatum demonstrates an association of PH4 with the biosynthetic function of dopaminergic nerve terminals. Reserpine and d-amphetamine in vivo elicited an increase and decrease, respectively, in striatal PH4 paralleling induced changes in synaptosomal DA synthesis. Other drugs altering central catecholaminergic function did not alter striatal PH4 levels significantly. The data suggest that 1) a major portion of total PH4 (as much as 90% in the striatum) is related to the function of catecholaminergic rather than serotonergic systems, 2) PH4 levels is a determinant of the velocity of DA synthesis and 3) PH4 levels are altered by some psychoactive drugs in association with changes in synaptosomal catecholamine biosynthetic rates.

Rat brain striatal reduced biopterin (BH4) levels vary diurnally by 2-fold, oscillating around a concentration of 3 micrometer. D-Amphetamine consistently induced a decrease in BH4 levels that did not exceed 25 to 30% with increasing doses; recovery of control levels required several hours. A large number of other psychotropic drugs, including other stimulants and phenylethylamine congeners, failed to induce a similar change. The amphetamine effect was blocked by methylphenidate and reserpine. The prolonged time for BH4 recovery could be explained by an amphetamine-induced functional uncoupling of quinonoid dihydropteridine reductase from striatal tyrosine hydroxylase as reported for various cofactor analogs, leading to spontaneous isomerization of the partially reduced pterin to its nonquinonoid form, which is not a substrate for the BH4 regenerating enzyme. If relevant to dopamine biosynthesis, such an uncoupling phenomenon might account for a unique neuropharmacology of the postamphetamine state.

The position here taken by the writer was assumed by him first in an article published in the New York Medical Record. On that occasion he expressed the opinion that the "great majority of observers had been led to consider syphilis the causative factor in the production of rectal stricture by the fact that this condition has most frequently been observed in syphilitic subjects." Since that time he has become more thoroughly convinced of the correctness of this view, and he still believes that it is much more rational to assume that syphilis is not immediately responsible for such lesions. The following reasons appear to him to justify the stand he has taken:Endarteritis is a well-recognized state in syphilis. This change in the vascular system, combined with the resultant low state of nutrition, renders the mucosa of the rectum less resistant to irritants and trauma. Under these circumstances small