Yukiko Makino

Presence of tetrahydroisoquinoline and 1-methyl-tetrahydro-isoquinoline in foods: Compounds related to Parkinson's disease

This is the first report confirming the presence of 1,2,3,4-tetrahydroisoquinoline (TIQ) and 1-methyl-1,2,3,4-tetrahydroisoquinoline(1MeTIQ) in a number of foods with a high 2-phenylethylamine content. These compounds were determined by gas chromatography-mass spectrometry. This study also confirmed that 1MeTIQ and TIQ can cross the blood-brain barrier in rat. Thus, these compounds, suspected to have relation to parkinsons disease, may accumulate in the brain from food sources.

1‐Methyl‐ 1,2,3,4‐Tetrahydroisoquinoline, Decreasing in 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine‐Treated Mouse, Prevents Parkinsonism‐Like Behavior Abnormalities

In l‐methyl‐4‐phenyl‐l,2,3,6‐tetrahydropyridine (MPTP)‐treated mouse brain, there was no significant increase or decrease in the content of an endogenous amine, 1,2,3,4‐tctrahydroisoquinoline (TIQ), which is well noted for inducing parkinsonism, whereas another endogenous amine, 1‐methyl‐1,2,3,4‐tetrahydroisoquinoline (1‐MeTIQ), was markedly reduced. This result agrees with the finding in human idiopathic parkinsonianism, confirmed by our previous research. In addition, pretreatment with 1‐MeTIQ completely prevented MPTP‐ or TIQ‐inducing bradykinesia, a symptom of parldnsonism. This study confirmed that 1‐MeTIQ plays an important role in preventing the pathogenesis of parldnsonism and is a possible leading compound of anti‐parkinsonism agents.

Novel Endogenous 1,2,3,4‐Tetrahydroisoquinoline Derivatives: Uptake by Dopamine Transporter and Activity to Induce Parkinsonism

Abstract: We designed as candidate metabolites and synthesized two 1‐benzyl‐1,2,3,4‐tetrahydroisoquinoline derivatives containing a dopamine moiety: 1‐(3′,4′‐dihydroxybenzyl)‐1,2,3,4‐tetrahydroisoquinoline (3′,4′‐DHBnTIQ) and 1‐benzyl‐6,7‐dihydroxy‐1,2,3,4‐tetrahydroisoquinoline (6,7DHBnTIQ). Both were detected in mouse brain as endogenous amines by gas chromatography/mass spectrometry. 3′,4′DHBnTIQ induced parkinsonism in mice when chronically administered intraperitoneally, whereas 6,7DHBnTIQ did not despite the structural similarity of the two compounds. This difference may be related to cellular uptake: In rat striatal synaptosomes, these compounds were intracellularly transported by the dopamine transporter with Km values of 6.14 and 7.82 µM and Vmax values of 214.3 and 112.2 pmol/min/mg of protein, respectively. Thus, endogenous 3′,4′DHBnTIQ may be actively transported into dopaminergic neurons and accumulated there, contributing at least in part to the induction of idiopathic Parkinsons disease.

Regional distribution of parkinsonism-preventing endogenous tetrahydroisoquinoline derivatives and an endogenous parkinsonism-preventing substance-synthesizing enzyme in monkey brain.

1,2,3,4-Tetrahydroisoquinoline (TIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), which exist in the brain of several mammalian species, are parkinsonism-inducing substances, and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ), which is enzymatically synthesized in rat brain, is a parkinsonism-preventing substance. In this study, we examined the regional distribution of contents of TIQ, 1MeTIQ, and 1BnTIQ, and activity of 1MeTIQ-synthesizing enzyme in monkey brain. The TIQ and 1BnTIQ contents in cerebrum and substantia nigra, and the 1MeTIQ contents in striatum and substantia nigra were higher than those in other brain regions, and 1MeTIQ-synthetic activity was high in cerebrum and thalamus. We speculate that 1MeTIQ-synthesizing enzyme may play an important role in idiopathic Parkinsons disease.

Metabolism and brain accumulation of tetrahydroisoquinoline (TIQ) a possible parkinsonism inducing substance, in an animal model of a poor debrisoquine metabolizer

4-Hydroxytetrahydroisoquinoline (4OH-TIQ) was detected as a metabolite of a possible parkinsonism-inducing substance, tetrahydroisoquinoline (TIQ), in rat liver microsomes and rat urine. Urinary excretion of 4OH-TIQ was significantly reduced in female DA rat, an animal model of a poor debrisoquine metabolizer. The female DA rat also showed significantly higher brain accumulation of TIQ. These results suggest that the metabolic detoxication process is depressed and TIQ accumulation in the brain is enhanced in a poor debrisoquine metabolizer, which may be one possible explanation for poor debrisoquine metabolizers being susceptible to Parkinsons disease.

Evaluation of rewarding effect of toluene by the conditioned place preference procedure in mice.

Toluene and many toluene-containing products are abused via inhalation. Previous investigations have used the place preference paradigm to evaluate the rewarding effects of commonly abused drugs such as morphine, cocaine, and amphetamine. A conditioning paradigm of toluene inhalation was developed in order to estimate the rewarding effect in mice. Conditioning sessions (five for toluene, five for air) were conducted twice daily for 5 days using a newly developed airtight inhalation shuttlebox (15x30x15 cm: wxlxh), which was divided into two compartments of equal size. One compartment was white with a textured floor, and the other was black with a smooth floor. All conditioning sessions were 20 min in duration, with a minimum of 7 h between sessions. Test sessions were carried out 1 day after the final training session with mice in a drug-free state. The time spent in each compartment during a 20-min session was measured using a digital video camera. Exposure to toluene vapors (700-3200 ppm) produced a significant conditioned place preference in mice. These results suggest that the conditioned place preference procedure using the newly developed airtight inhalation shuttlebox constitutes an important tool for studying the rewarding effect of abused solvents.

Use of stable isotope ratios for profiling of industrial ephedrine samples: Application of hydrogen isotope ratios in combination with carbon and nitrogen

The utility of hydrogen stable isotope ratio measurement by IR-MS for establishing the origin of ephedrine and pseudoephedrine (ephedrines), precursors of methamphetamine, was evaluated. There are two kinds of commercial semisynthetic ephedrines, one produced from molasses and the other from pyruvic acid. While the semisynthetic ephedrines derived from pyruvic acid cannot be discriminated from biosynthetic ephedrines and synthetic ephedrines based on delta(13)C and delta(15)N values, they could be identified from the delta(2)H values. The low deuterium content of biosynthetic ephedrines (delta(2)H: -193 to -151 per thousand) allows a clear distinction from synthetic ephedrines (delta(2)H: -73 to -30 per thousand), semisynthetic ephedrines derived from pyruvic acid (delta(2)H: +75 to +148 per thousand) and semisynthetic ephedrines derived from molasses (delta(2)H: -74 to +243 per thousand). The wide range of delta(2)H values of semisynthetic ephedrines is therefore very useful for the detailed classification of ephedrines, in combination with the measurement of delta(13)C and delta(15)N values as described in our previous work. This study was carried out on a limited number of samples reflecting the various routes of ephedrines manufacture. But it has become apparent that this stable-isotope analysis is an appropriate means by which to screen for manufacturing process of ephedrines. This approach should be useful for worldwide precursor control of methamphetamine.

Impurity profiling of ephedrines in methamphetamine by high-performance liquid chromatography

Separation of the enantiomers and diastereomers of ephedrines was investigated for impurity profiling of methamphetamine. We describe a method for the analysis of (1S,2R)-(+)-ephedrine, (1R,2S)-(-)-ephedrine, (1S,2S)-(+)-pseudoephedrine and racemic methylephedrine in bulk methamphetamine by HPLC using two different columns: a phenyl-beta-cyclodextrin-type column and an ODS-type column. The analytes were detected by UV absorbance measurement at 210 nm. As little as 0.05% of each ephedrine in bulk methamphetamine could be determined. In the impurity profiling of methamphetamine, the identification of ephedrines may provide valuable information about the precursor. This method was confirmed to be sufficiently sensitive to identify trace amounts of (1R,2S)-(-)-ephedrine and (1S,2S)-(+)-pseudoephedrine in bulk methamphetamine synthesized by the Emde method.

Enantiomeric separation of amphetamine by high-performance liquid chromatography using chiral crown ether-coated reversed-phase packing: application to forensic analysis

d-Amphetamine and l-amphetamine were clearly separated by HPLC analysis using a chiral crown ether column (CROWNPACK CR(+)). As little as 0.1% d-amphetamine in bulk methamphetamine could be determined. The enantiomeric form of the by-product in a drug sample may be helpful in evaluating the possibility of illicit synthesis. When the isomeric composition of amphetamine present in urine from a methamphetamine abuser was examined, only d-amphetamine was detected as a metabolite. The present method was also applied to the enantiomeric separation of norephedrine.

A Novel and Neurotoxic Tetrahydroisoquinoline Derivative In Vivo: Formation of 1,3-Dimethyl-1,2,3,4-Tetrahydroisoquinoline, a Condensation Product of Amphetamines, in Brains of Rats Under Chronic Ethanol Treatment

Abstract: Repeated amphetamine administration to rats under chronic ethanol intoxication resulted in the formation of 1,3‐dimethyl‐1,2,3,4‐tetrahydroisoquinoline (1,3‐DiMeTIQ), a novel metabolite of amphetamines. 1,3‐DiMeTIQ was quantified with a sensitive, specific assay using gas chromatography‐mass spectrometry. It was not found in the brains of rats given repeated amphetamine administration but no ethanol. The chronic ethanol‐intoxicated rats subjected to repeated amphetamine administration exhibited behavioral abnormalities, such as repeated convulsions and curving of the back. 1,3‐DiMeTIQ contents were markedly higher in the brain or plasma of rats manifesting abnormal behavior in comparison with those in rats behaving normally. Thus, the 1,3‐DiMeTIQ content in the rat brain seems to have some relationship with behavioral abnormalities. This study also confirmed that 1,3‐DiMeTIQ can cross the blood‐brain barrier in the rat. Intraperitoneal 1,3‐DiMeTIQ injections to rats caused behavioral symptoms similar to those observed in rats with chronic ethanol intoxication and repeated amphetamine administration. The effect of toxic doses of 1,3‐DiMeTIQ on dopaminergic and serotonergic metabolism in the whole rat brain was also investigated.