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

doi:10.1016/0024-3205(90)90128-E

Life Sciences

Volume 46, Issue 8, 1990, Pages 599-605

https://doi.org/10.1016/0024-3205(90)90128-E Get rights and content

Abstract

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 Parkinson's disease.

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Cited by (59)

N-methyltetrahydropyridines and pyridinium cations as toxins and comparison with naturally-occurring alkaloids
2016, Food and Chemical Toxicology
Citation Excerpt :
TIQ and 1-Me-TIQ are metabolized to 4-hydroxy-TIQs by CYP2D6 and in small amounts to N-methyl-TIQs, isoquinoline and 3,4-dihydroisoquinoline (Kikuchi et al., 1991; Nagatsu, 2002). Initial studies in rats suggested that poor metabolizers of CYP2D lead to long-lasting accumulation of TIQs in brain (Ohta et al., 1990). However, biotransformation efficiency of TIQs through 4-hydroxylation is poor and has no influence in the brain levels whereas N-Me-TIQ is not apparently hydroxylated by human CYP2D6 (Herraiz et al., 2006; Lorenc-Koci, 2012).
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 1-methyl-4-phenylpyridinium cation (MPP⁺) are selective dopaminergic neurotoxins producing Parkinsonism. MPTP is activated by monoamine oxidase-B (MAO-B) to MPP⁺ that inhibits mitochondrial function. Molecules resembling MPTP which afford pyridinium cations are also neurotoxins. The herbicide paraquat (a bipyridinium dication) and the naturally-occurring β-carboline and isoquinoline alkaloids are structural analogues of MPTP/MPP⁺. Paraquat generates reactive oxygen species (ROS) producing neurotoxicity by a mechanism that differs from MPTP/MPP⁺. Human exposure to PQ is increasingly associated with neurodegeneration. Tetrahydro-β-carbolines (THβCs), β-carbolines (βCs) and tetrahydroisoquinolines (TIQ_s) are bioactive compounds occurring in foods and the human body. They are not MPTP-like toxins and do not appear to induce neurotoxicity at normal levels of exposure. Among TIQs, endogenous dopamine-derived TIQs (i.e. salsolinol) and 1-benzyl-TIQ are toxic through ROS generation. In contrast, β-carbolinium (βC⁺s) and isoquinolinium cations (IQ⁺s) are neurotoxicants resembling MPP⁺ although they are less potent and selective. βC⁺s and IQ⁺s have been detected in the human brain but their toxicological significance remains unknown. THβCs/βCs and TIQs are activated to toxic cations by N-methyltransferases (NMT) and/or heme peroxidases and are metabolized by cytochrome P450 enzymes. Remarkably, recent findings suggest, instead, that βCs and TIQs are neuroprotectants and neurorestorative, raising the interest of these molecules.
Inhibition of rat liver CYP2D in vitro and after 1-day and long-term exposure to neuroleptics in vivo - Possible involvement of different mechanisms
2005, European Neuropsychopharmacology
The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2D measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally (ip) for 1-day or 2-weeks (twice a day) with pharmacological doses of the drugs (promazine, levomepromazine, thioridazine, perazine 10 mg kg⁻¹; chlorpromazine 3 mg kg⁻¹; haloperidol 0.3 mg kg⁻¹; risperidone 0.1 mg kg⁻¹; sertindole 0.05 mg kg⁻¹), in the absence of the neuroleptics in vitro. Neuroleptics added in vitro to control liver microsomes decreased the activity of the rat CYP2D by competitive or mixed inhibition of the enzyme. Thioridazine (K_i=15 μM) was the most potent inhibitor of the rat CYP2D among the drugs studied, whose effect was more pronounced than that of the other neuroleptics tested: phenothiazines (K_i=18–23 μM), haloperidol (K_i=32 μM), sertindole (K_i=51 μM) or risperidone (K_i=165 μM). The investigated neuroleptics—when given to rats in vivo—also seemed to exert an inhibitory effect on CYP2D via other mechanisms. One-day exposure of rats to the classic neuroleptics decreased the activity of CYP2D in rat liver microsomes. After chronic treatment with the investigated neuroleptics, the decreased CYP2D activity produced by the phenothiazines was still maintained, while that caused by haloperidol diminished. Moreover, risperidone decreased the activity of that enzyme. The obtained results indicate drug- and time-dependent interactions between the investigated neuroleptics and the CYP2D subfamily of rat cytochrome P-450, which may proceed via different mechanisms: (1) competitive or mixed inhibition of CYP2D shown in vitro, the inhibitory effects of phenothiazines being stronger than those of haloperidol or atypical neuroleptics, but weaker than the effects of the respective drugs on human CYP2D6; (2) in vivo inhibition of CYP2D, produced by both 1-day and chronic treatment with phenothiazines, which suggests inactivation of enzyme by intermediate metabolites; (3) in vivo inhibition of CYP2D by risperidone, produced only by chronic treatment with the drug, which suggests its influence on the enzyme regulation.
Effect of 1,2,3,4,-tetrahydroisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [<sup>3</sup>H]GBR 12,935 to dopamine transporter in the rat nigrostriatal, dopaminergic system
2004, Brain Research
Citation Excerpt :
On the other hand, females of Dark Agouti rats, which carry a genetic defect in one member of CYP2D subfamily that metabolizes debrisoquine, are more sensitive to the neurotoxic action of MPTP [27]. Concerning TIQ toxicity, Ohta et al. [58] have found that the plasma and brain levels of this compound after its p.o. administration were higher in females than in males of that strain; hence, it has been postulated that TIQ accumulation in the brain of poor debrisoquine metabolizers in humans may be connected with the increased susceptibility to triggering PD. However, there are no experimental data available which would evidence that parkinsonian-like symptoms are more distinctly pronounced in the CYP2D deficient rats treated chronically with TIQ than in those without this defect.
Current concepts of Parkinson's disease (PD) postulate that interaction between neurotoxins and specific genetic background may play an important role in pathogenesis of PD. Therefore, the effect of multiple administration of 1,2,3,4-tetrahydroisoquinoline (TIQ) under conditions of CYP2D blockade on the expression of key markers of PD was studied in the rat striatum (STR) and substantia nigra (SN). TIQ administered alone (50 mg/kg i.p. twice daily for 14 days) markedly decreased the level of tyrosine hydroxylase protein (TH) in the STR; however, this effect was not accompanied by reduction of dopamine (DA) concentration and [³H]GBR 12,935 binding to dopamine transporter (DAT). Administration of CYP2D inhibitor, quinine, jointly with TIQ lowered the levels of TH and DA in that structure, but slightly increased DAT binding. In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [³H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc). Neither the TH level nor DA concentration was affected by the combined treatment, although DAT binding was still reduced in the SN. TIQ did not change the total DA catabolism in the STR, but caused its inhibition in the SN. It strongly depressed the levels of intraneuronal DA metabolite DOPAC and enhanced that of extraneuronal 3-MT in either structure. TIQ more weakly affected the levels of both DA metabolites in the presence of quinine. Our results suggest that endogenous TIQ may act rather as neuromodulator but not as parkinsonism-inducing neurotoxin in the rat brain.
Disposition of 1,2,3,4,-tetrahydroisoquinoline in the brain of male Wistar and Dark Agouti rats
2004, Brain Research
Citation Excerpt :
Our complementary study with verapamil supports the view that P-gp contributes to the elimination of TIQ from the rat brain and body since it increases TIQ levels both in the brain and plasma; the latter effect must to be connected with inhibition of P-gp function in the rat kidney [34]. Hence, we suppose that the accumulation of TIQ in the human brain, postulated previously as a risk factor of PD [50], may be coupled rather with a genetic defect of P-gp than with that of CYP2D. In line with this view, Furuno et al. [13] have recently shown that frequency of 3435T/T genotype, which is associated with decreased P-gp expression and function, was higher in parkinsonian patient with both early- and late-onset disease than in healthy controls.
Direct evidence for accumulation of 1,2,3,4-tetrahydroisoquinoline (TIQ), an endo- and exogenous substance suspected of producing Parkinsonism in humans, has not yet been shown. This study aimed to examine TIQ disposition in the whole rat brain and in the striatum and substantia nigra (SN). TIQ was administered to male Wistar and Dark Agouti rats (20, 40 and 100 mg/kg i.p.) alone or jointly with specific CYP2D inhibitor quinine (20, 40, 80 mg/kg i.p.), acutely or chronically. TIQ concentration in brain of both strains was several-fold higher than in plasma. The level of its metabolite, 4-OH-TIQ, was very low in the brain and plasma of TIQ-treated Wistar while in those receiving additionally quinine or in Dark Agouti rats, 4-OH-TIQ was absent or negligible. Inhibition of CYP2D catalyzing TIQ 4-hydroxylation in the liver had no influence on TIQ accumulation in the brain. Exogenous TIQ was actively transported from periphery into the brain by the organic cation transporter system, mainly OCT3, and quickly eliminated from it by P-glycoprotein. TIQ accumulation after chronic injection to Wistar rats was short-lasting and limited to SN. High concentration of TIQ in SN induces while in the liver inhibits the nigral and hepatic activity CYP2D, respectively.
1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, induces dopaminergic cell death through apoptosis
2003, NeuroToxicology
Endogenous MPTP-like neurotoxins such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) have been suspected in the etiology of Parkinson’s disease (PD). 1BnTIQ was found in a concentration three times higher in cerebrospinal fluid of PD brains than control subjects [J. Neurochem. 65 (6) (1995) 2633]. In the present study, we have evaluated the mechanisms of 1BnTIQ toxicity in human dopaminergic SH-SY5Y cells and tested the neuroprotective action of SKF-38393, a dopamine receptor (D₁) agonist. 1BnTIQ dose dependently decreased cell viability in dopaminergic SH-SY5Y cells and the extent of cell death was more pronounced when compared to MPP⁺. Similar to MPP⁺, 1BnTIQ significantly decreased [ $^{3} H$ ]dopamine uptake. 1BnTIQ significantly increased lipid peroxidation, Bax expression, and active caspase-3 formation. Furthermore, it decreased the expression of Bcl-xL, an anti-apoptotic protein, in these cells. SKF-38393, a dopamine receptor (D₁) agonist (1 and 10 μM) completely prevented the cell death and significantly increased cell viability. These results strongly suggest that 1BnTIQ induces dopaminergic cell death by apoptosis and dopamine receptor agonists may be useful neuroprotective agents against 1BnTIQ toxicity.
Stereochemical studies on the synthesis of 1,2,3,4- tetrahydroisoquinolin-4-ols
1998, Tetrahedron Asymmetry
The stereoselectivity of the acid catalyzed promoted cyclization of adequately substituted α-aminoaldehydes to afford a series of tetrahydroisoquinolin-4-ols is studied. The results illustrate the effect of the substituents at C-1 and/or C-3 in the target heterocycle. The required precursors 5 and 10 were synthesized from the enantiomerically pure (−)-imines 1 by two different routes, and reacted with conc. HCl.

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

Abstract

Neurosci. Lett.

Gen. Pharmacol.

Neurosci. Lett.

Neurosci. Lett.

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

Life Sci.

Lancet

J. Biol. Chem.