OBJECTIVE: Tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. Because the TH Val81Met polymorphism is located in the amino-terminal regulatory domain of the tetrameric enzyme, it is a candidate marker for susceptibility to dopamine-related traits. We investigated the hypothesis that TH Val81Met polymorphism can influence susceptibility to tardive dyskinesia (TD) in schizophrenia. METHODS: TH Val81Met polymorphism was analyzed by PCR-based methods in 83 schizophrenic patients with TD and 126 schizophrenic patients without TD, matched for antipsychotic drug exposure and other relevant variables. RESULTS: There was no significant association of the genotype and allele frequencies determined by the TH Val81Met polymorphism between TD and non-TD patients. In addition, there was no significant difference in terms of total Abnormal Involuntary Movement Scale scores among the three genotype groups. CONCLUSION: Within the limitations imposed by the size of the clinical sample, these findings suggest that the Val81Met polymorphism of the TH gene does not contribute significantly to the risk for TD.
Dopamine ; Dyskinesias ; Gene Frequency ; Genotype ; Humans ; Movement Disorders ; Schizophrenia ; Tyrosine ; Tyrosine 3-Monooxygenase

One of the major pathophysiological features of primary hypertension is an inappropriate activation of the sympathetic nervous system, which is mediated by excessive synthesis and secretion of catecholamine into the blood. Tyrosine hydroxylase (TH), a rate-limiting enzyme in the synthesis of catecholamine, has been highlighted because genetic variations of TH could alter the activity of the sympathetic nervous system activity and subsequently contribute to the pathogenesis of hypertension. Here, we discuss the role of TH as a regulator of sympathetic activity and review several studies that investigated the relationship between genetic variations of TH and hypertension.
Genetic Variation* ; Hypertension* ; Polymorphism, Single Nucleotide ; Sympathetic Nervous System ; Tyrosine 3-Monooxygenase* ; Tyrosine*

Fetal dopaminergic or nondopaminergic cortical tissues were implanted directly into the denervated striatum of partial lesioned rat parkinsonian models. After transplantation, at rats were behaviourally tested with apomorphine and sacrificed for tyrosine hydroxylase immunohistochemical stain. The results of this study are summarized as follows : 1) Of 45 rats partially lesioned with 6-hydroxydopamine, 17 rats(37.8%) met a criteria(a minimum of 4 times/min to apomorphine-induced rotation test) of the rat parkinsonian model. 2) Eight weeks after transplantation of the fetal dopaminergic tissues into the striatum of the rat parkinsonian model, transplanted dopaminergic cells were found to be alive. Also reinnervated dopaminergic fibers were found in the previously denervated striatum. And the behavioural study suggested that the transplantation of the fetal dopaminergic neurons had influenced on the apomorphine-induced rotation. 3) Eight weeks after transplantation of the fetal nondopaminergic tissues into the striatum of the rat parkinsonian model, dopaminergic cells were not found in the previously denervated striatum. However, reinnervation of the dopaminergic fibers were found in the preciously denervated striatum. However, reinnervation of the dopaminergic fibers were found in the previously denervated striatum as well as the reduction of the apomorphine-induced rotation compared to the pregraft state. The major finding of this study support a trophic hypothesis for the mechanism of recovery in response to fetal dopaminergic or nondopaminergic tissue. The author conclude that fetal nondopaminergic tissue also had some beneficial effect in reducing apomorphine-induced rotational asymmetry probably by promoting recovery or sprouting of remaining dopaminergic fibers at the previously denervated striatum of the rat parkinsonian model.
Animals ; Apomorphine ; Dopaminergic Neurons ; Oxidopamine ; Rats* ; Tissue Transplantation* ; Transplantation ; Transplants* ; Tyrosine 3-Monooxygenase

The electrophysiological effects of N-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine(NMPTP), a chemical inducer of Parkinsonism in man and monkey, on the pigmented rabbit retina were determined under acute condition. The amplitude of the b-wave of the rabbit electroretinogram was affected, but both the implicit time and half-amplitude duration of it were not. The amplitude of the photopic b-wave was increased by 72.9 +/- 32.1% 5 hours after NMPTP administration(P[t]<0.05), Whereas the scotopic b-wave was decreased by 31.2 +/- 6.4% 4 hours after injection(P[t]<0.05). The above results suggest or support that: (1) the dopaminergic amacrine cells are related to the modulation of the b-wave of the rabbit electroretinogram. (2) during light adaptation, the dopaminergic amacrine cells uncouple the rod and cone systems in the inner plexiform layer and are involved in functions of the rod system. (3) the hypothesis that the function of tyrosine hydroxylase may be affected by NMPTP.
Adaptation, Ocular ; Amacrine Cells ; Haplorhini ; Parkinsonian Disorders ; Rabbits* ; Retina ; Tyrosine 3-Monooxygenase

PURPOSE: A sensitive assay to detect minimal residual disease in neuroblastoma is necessary for accurate assessment of disease status and optimal treatment. In this study, we compared the usefulness of sensitive methods, flow cytometry and RT-PCR for the detection of minimal residual disease in neuroblastoma. METHODS: Eighteen patients who were newly diagnosed and treated at Severance Hospital since 1999 were included in this study. Samples from bone marrow, peripheral blood, and peripheral blood stem cell product were examined for tumor cell contamination by RT-PCR (TH RT-PCR) to detect tyrosine hydroxylase mRNA and by flow cytometry identifying CD9+/CD56+/CD45- cells. RESULTS: We analyzed 20 cases from 18 patients, which were assayed by both methods at the same time. Among 20 cases, 16 cases showed same results, which were compatible with histologic results and clinical course, and 4 cases showed different results. One case of them showed positive result in histology and flow cytometry, but negative result in TH RT-PCR. The other 3 cases showed negative results in flow cytometry, but positive results in TH RT-PCR, and 1 patient of them relapsed. Among 16 patients, 2 patients, showing positive results in only TH RT-PCR, relapsed. CONCLUSION: Detection of minimal residual disease using TH RT-PCR and flow cytometry was effective and useful in evaluating disease status and deciding for proper treatment.
Bone Marrow ; Flow Cytometry* ; Humans ; Neoplasm, Residual* ; Neuroblastoma* ; RNA, Messenger ; Stem Cells ; Tyrosine 3-Monooxygenase

Astragalus Membranaceus (AM) is a useful Korean herb that has been clinically prescribed for stress-related illness. The objective of the present study was to examine the anti-stress effects of AM on repeated stress-induced alterations of anxiety, learning and memory in rats. Restraint stress was administered for 14 days (2h/day) and AM (400mg/kg) given by oral administration, in the AM group, for the same period. Starting on the eighth day, the rats were tested for spatial memory on the Morris water maze test (MW) and for anxiety on the elevated plus maze (EPM). Changes of expression on immunohistochemistry were studied for cholineacetyl transferase (ChAT) and tyrosine hydroxylase (TH) in the brain. The results showed that the rats treated with AM had significantly reduced stress-induced deficits on learning and memory on the spatial memory tasks. In addition, the ChAT immunoreactivities were increased. In the EPM, treatment with AM increased the time spent in the open arms (p<0.001) compared to the control group. In addition, AM treatment also normalized increases of TH expression in the LC (p<0.001). In conclusion, administration of AM improved spatial learning and memory and reduced stress-induced anxiety. Thus, the present results suggest that AM is able to recover behavioral and neurochemical impairments induced by stress.
Administration, Oral ; Animals ; Anxiety ; Arm ; Astragalus membranaceus ; Brain ; Immunohistochemistry ; Learning ; Memory ; Rats ; Transferases ; Tyrosine 3-Monooxygenase

This study investigated the effects of ombuoside, a flavonol glycoside, on dopamine biosynthesis in PC12 cells. Ombuoside at concentrations of 1, 5, and 10 µM increased intracellular dopamine levels at 1 – 24 h. Ombuoside (1, 5, and 10 µM) also significantly increased the phosphorylation of tyrosine hydroxylase (TH) (Ser40) and cyclic AMP-response element binding protein (CREB) (Ser133) at 0.5 – 6 h. In addition, ombuoside (1, 5, and 10 µM) combined with L-DOPA (20, 100, and 200 µM) further increased intracellular dopamine levels for 24 h compared to L-DOPA alone. These results suggest that ombuoside regulates dopamine biosynthesis by modulating TH and CREB activation in PC12 cells.
Animals ; Carrier Proteins ; Dopamine ; Levodopa ; PC12 Cells ; Phosphorylation ; Tyrosine 3-Monooxygenase

BACKGROUND: For the treatment of Parkinson's disease, dopamine-producing cells or genes involved in producing dopamine or supporting neurons have been tested to replace conventional chemical therapies. Of these, tyrosine hydroxylase (TH) was the most widely used gene for the therapy. Trials using TH via various vectors yielded behavioral improvements in animal models but the effectiveness did not last long enough. As one of the approaches for solving this problem, the regulation of expression of the protein and mRNA of TH was studied. METHODS: Two approaches for a higher and/or more stable expression of TH were pursued. First, the effect of cofactor tetrahydrobiopterin (BH4) on the expression level of TH and second, the effect of deletion which enables TH protein to escape from protease attack, were examined. RESULTS: Cells producing BH4 showed an approximately 10-fold higher TH expression than cells expressing TH alone. When the in vitro modified TH was expressed in NIH-3T3, mutant THs showed elevated protein (17.5 ~68.6 fold) and mRNA (1.8 ~4.6 fold) expression levels at a steady state. CONCLUSIONS: Results suggest that an addition of BH4 has a more positive effect on mRNA expression levels than protein. However, the deletions seem to have a tremen-dous effect on the translation and/or protein stability, but a small effect on the mRNA level. (J Korean Neurol Assoc 19(5):514~519, 2001)
Dopamine ; Models, Animal ; Neurons ; Parkinson Disease ; Phosphorylation ; Protein Stability ; RNA, Messenger ; Tyrosine 3-Monooxygenase* ; Tyrosine* ; United Nations

OBJECTIVES: Tyrosine hydroxylase(TH) is a rate-limiting enzyme in the synthesis of catecholamines, and could be a candidate gene for causing the bipolar disorders. Therefore, we designed this study to investigate the association of the VNTR(variable number of tandem repeats) polymorphic locus in the first intron of the TH gene with bipolar disorders. METHODS: We typed VNTB polymorphic region of the TH gene using PCR in 115 bipolar patients and 85 normal controls. Four types of alleles(A, B, C, D) were typed according to the difference of the repeat(TCAT)6-9 number. The frequencies of allele and genotype were compared between patients and normal controls, and in patients and normal controls allelic frequencies were compared respectively in terms of family history of affective disorders and age of onset. RESULTS: 1) The allelic frequencies were significantly lower in type A, and significantly higher in type D in patient group compared to control group. The genotype frequencies were significantly higher in type BD in patient group than in control group. 2) In comparing the allelic frequencies among patient group with and without family history and control group, there were no significant differences between groups with and without family history, whereas patient group with family history showed lower significance in type A and higher significance in type D compared to control group. 3) In comparing the allelic frequencies among patient groups with early onset and late onset and control group, patient group with early onset showed higher significance in type D than patient group with late onset and showed lower significance in type A and higher significance in type D compared to control group. CONCLUSIONS: The authors conclude that the VNTR polymorphic region of the TH gene might be associated bipolar disorders, and type A and type D alleles might be susceptibility genes of bipolar disorder.
Age of Onset ; Alleles ; Bipolar Disorder ; Catecholamines ; Genotype ; Humans ; Introns ; Mood Disorders ; Polymerase Chain Reaction ; Tyrosine 3-Monooxygenase* ; Tyrosine*

OBJECTIVE: Restless legs syndrome (RLS) has been reported to be more prevalent in schizophrenic patients who take antipsychotics. The cause of RLS is unknown but associated with dopaminergic deficiency. Tyrosine hydroxylase (TH) is the enzyme responsible for catalyzing the conversion of L-tyrosine to DOPA. The purpose of this study is to determine whether the TH gene Val81Met polymorphism is associated with antipsychotic-induced RLS. METHODS: One hundred ninety Korean schizophrenic patients were evaluated by the diagnostic criteria of the International RLS Study Group (IRLSSG). The genotyping was performed by PCR-based methods. RESULTS: Of the one hundred ninety schizophrenic patients, 44 (23.2%) were found to have RLS. Although there were no significant associations between TH genotypes or allele frequencies and RLS, when separate analyses were performed by sex (male or female), we detected significant differences in the frequencies of the genotype (chi-square=6.15, p=0.046) and allele (chi-square=4.67, p=0.031) of the TH gene Val81Met polymorphism between those with and without RLS in the female patients. CONCLUSION: These findings suggest that the TH gene Val81Met SNP might be associated with antipsychotic-induced RLS in female schizophrenic patients.
Alleles ; Antipsychotic Agents ; Dihydroxyphenylalanine ; Female ; Gene Frequency ; Genotype ; Humans ; Restless Legs Syndrome ; Schizophrenia ; Tyrosine ; Tyrosine 3-Monooxygenase