Inhibition of monoamine synthesis by irreversible blockade of aromatic aminoacid decarboxylase with α-monofluoromethyldopa

Jung, Michael J.; Palfreyman, Michael G.; Wagner, Joseph; Bey, Philippe; Ribéreau-Gayon, G.; Zraïka, M.; Koch‐Weser, Jan

doi:10.1016/0024-3205(79)90324-2

Cited by 59 publications

(25 citation statements)

References 12 publications

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“…Therefore, the possibility that metabolites of 5-HTP other than 5-HT may contribute to the development of 5-HTP-induced hypoglycaemia cannot be excluded. In the present study, I tested the effect of x-monofluoromethyldopa (FMD), a potent irreversible inhibitor of aromatic amino acid decarboxylase (Kollonitsch et al, 1978;Jung et al, 1979), on 5-HTP-induced hypoglycaemia.…”

Section: Introductionmentioning

confidence: 99%

Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

Endo¹

1987

British J Pharmacology

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Experiments were done to examine whether the accumulation of 5‐hydroxytryptamine (5‐HT) in the liver is responsible for the hypoglycaemia induced in mice by 5‐hydroxytryptophan (5‐HTP) and lipopolysaccharides (LPS). (±)‐α‐Monofluoromethyldopa (FMD), a potent irreversible inhibitor of aromatic amino acid decarboxylase, suppressed the 5‐HTP‐induced accumulation of 5‐HT in the liver at a dose of 2 mg kg−1 or more, but potentiated the accumulation at a lower dose of 0.4 mg kg−1. Corresponding to these effects, the hypoglycaemic response was prevented by the higher doses of FMD and potentiated by the lower dose. These contrasting effects of FMD were explicable by the amounts of 5‐HTP entering the liver. In contrast, FMD did not prevent either the hypoglycaemia or the accumulation of 5‐HT in the liver induced by LPS. These results further support the hypothesis that the accumulation of 5‐HT in the liver is causally related to the hypoglycaemia induced by 5‐HTP and indicate that the LPS‐induced 5‐HT accumulation in the liver is not derived from stimulation of 5‐HT synthesis. It is still not clear whether the accumulation of 5‐HT in the liver is involved in the hypoglycaemic response to LPS.

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Section: Introductionmentioning

confidence: 99%

Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

Endo¹

1987

British J Pharmacology

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“…This decrease was not as dramatic as expected. However, when MFMdopa was used at 100 mg/Kg, dopa has been shown to accumulate for 8 h in brain tissue (Jung et al, 1979). Under the same conditions, the clearance of [ 3 H]-MFMdopa may be the same as dopa, which would explain why we still observed a moderate amount of radioactivity in the LC 7 h after the in vivo inhibition of AADC.…”

Section: Discussionmentioning

confidence: 80%

In situ examination of tyrosine hydroxylase activity in the rat locus coeruleus using (3?,5?)-[3H2]-?-fluoromethyl-tyrosine as substrate of the enzyme

Bezin

Marcel

Garcia

et al. 2000

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Tyrosine hydroxylase (TH) activity can be modified by changes in the specific activity of the enzyme (SA(TH)) or in the levels of active enzyme. We developed a methodology making it possible to measure with excellent anatomical resolution TH enzymatic activity and TH protein quantity by quantitative autoradiography and immunoautoradiography, respectively, from adjacent sections taken at serial intervals along the longitudinal extent of a same brain. SA(TH) was estimated by the slope of linear regressions established between TH activity and TH quantity measured at each anatomical plane. To evaluate TH activity, we used (3',5')-[(3)H(2)]-(D, L)-alpha-fluoromethyl-tyrosine [(3)H(2)]-MFMT, which is transformed by TH to [(3)H]-MFM-dopa, a potent and irreversible substrate for aromatic amino acid decarboxylase. We found that the SA(TH) in the cell body area of the LC (PKA) was 48% lower than that evaluated in the surrounding pericoerulean neuropil (PCN). In the PCN, 22% only of TH level exhibited a level of enzymatic activity above threshold. We also examined how SA(TH) was distributed in the LC 15 min and 3 days after RU 24722 treatment, a potent phasic and tonic activator of TH enzyme in noradrenergic neurons. Two distinct mechanisms have been observed: the short-term effect was due to an increase in the SA(TH) in the PKA only, while the long-term effect was mainly caused by an increase in the number of active TH proteins in the PCN. These results suggest that the fine regulation of TH activity which occurs in the different compartments of LC neurons may be critical in the functions involving the LC.

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“…MFMD is the first inhibitor of AADC potent enough to make decarboxylation the rate-limiting step in catecholamine and 5-HT synthesis and to deplete tissue monoamines (Jung et al, 1979a). From the relative activities of tyrosine hydroxylase and AADC (Jung et al, 1979a) it is possible to calculate that AADC activity in mouse brain must be 99%O inhibited before it becomes rate-limiting.…”

Section: Discussionmentioning

confidence: 99%

“…From the relative activities of tyrosine hydroxylase and AADC (Jung et al, 1979a) it is possible to calculate that AADC activity in mouse brain must be 99%O inhibited before it becomes rate-limiting. MFMD does not inhibit tyrosine hydroxylase (Jung et al, 1979a (Figure 2) but the concentration of 5-HTP is markedly elevated (unpublished). This strongly suggests that MFMD does not modify the synthesis of 5-HT by reducing the availability of its natural precursor, tryptophan or by inhibiting its hydroxylation.…”

Section: Discussionmentioning

confidence: 99%

“…We have recently found that DL-amonofluoromethyldopa (MFMD, RMI 71963) is a potent enzyme-activated, irreversible inhibitor of AADC: when administered to mice it greatly decreases the concentrations of dopamine, noradrenaline and 5-HT in brain, heart and kidney (Jung, Pal-freyman, Wagner, Bey, Ribereau-Gayon, Zraika & Koch-Weser, 1979a). The present studies were undertaken to characterize further the monoaminedepleting effects of MFMD as functions of dose and duration of treatment.…”

Section: Introductionmentioning

confidence: 99%

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Further Studies on the Inhibition of Monoamine Synthesis by Monofluoromethyldopa

Bey

Jung

Koch‐Weser

et al. 1980

British J Pharmacology

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α‐Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme‐activated irreversible inhibitor of aromatic l‐amino acid decarboxylase produces a substantial and long‐lasting decrease in the catecholamine content of mouse brain, heart and kidney. Single doses of MFMD reduce the 5‐hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration. In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.

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Inhibition of monoamine synthesis by irreversible blockade of aromatic aminoacid decarboxylase with α-monofluoromethyldopa

Cited by 59 publications

References 12 publications

Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

Suppression and potentiation of 5‐hydroxytryptophan‐induced hypoglycaemia by α‐monofluoromethyldopa: correlation with the accumulation of 5‐hydroxytryptamine in the liver

In situ examination of tyrosine hydroxylase activity in the rat locus coeruleus using (3?,5?)-[3H2]-?-fluoromethyl-tyrosine as substrate of the enzyme

Further Studies on the Inhibition of Monoamine Synthesis by Monofluoromethyldopa

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