Determination of tetrahydropapaveroline in the urine of Parkinsonian patients receiving l-dopa—carbidopa (Sinemet) therapy by high-performance liquid chromatography

Cashaw, Jesse L.

doi:10.1016/0378-4347(93)80141-p

Cited by 21 publications

(19 citation statements)

References 13 publications

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“…The regiochemistry of THP with four phenolic hydroxyl groups suggests a precursory relationship to morphine alkaloids. Indeed this potential role as precursor for morphine had already been suggested (13,17,21,23,(26)(27)(28)), but never experimentally tested. This attractive hypothesis was investigated to see whether THP is transformed by live mice into a phenolcoupled morphine precursor.…”

Section: Resultsmentioning

confidence: 99%

Urinary excretion of morphine and biosynthetic precursors in mice

Grobe

Lamshöft

Orth³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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It has been firmly established that humans excrete a small but steady amount of the isoquinoline alkaloid morphine in their urine. It is unclear whether it is of dietary or endogenous origin. There is no doubt that a simple isoquinoline alkaloid, tetrahydropapaveroline (THP), is found in human and rodent brain as well as in human urine. This suggests a potential biogenetic relationship between both alkaloids. Unlabeled THP or [1;3; ]-THP was injected intraperitoneally into mice and the urine was analyzed. This potential precursor was extensively metabolized (96%). Among the metabolites found was the phenol-coupled product salutaridine, the known morphine precursor in the opium poppy plant. Synthetic [7D]-salutaridinol, the biosynthetic reduction product of salutaridine, injected intraperitoneally into live animals led to the formation of [7D]-thebaine, which was excreted in urine. [N-CD 3 ]-thebaine was also administered and yielded [N-CD 3 ]-morphine and the congeners [N-CD 3 ]-codeine and [N-CD 3 ]-oripavine in urine. These results show for the first time that live animals have the biosynthetic capability to convert a normal constituent of rodents, THP, to morphine. Morphine and its precursors are normally not found in tissues or organs, presumably due to metabolic breakdown. Hence, only that portion of the isoquinoline alkaloids excreted in urine unmetabolized can be detected. Analysis of urine by high resolution-mass spectrometry proved to be a powerful method for tracking endogenous morphine and its biosynthetic precursors.endogenous morphine | mammalian mophine | morphine biosynthesis | stable-isotope labeled morphine | high resolution-mass spectrometry T he occurrence of endogenous morphine in mammals has been a controversy over the past three decades. Goldstein (1-3) and Spector (4-7) and their associates pioneered the assumption that morphine occurs in mammals and plays an unknown role. Other groups claimed that the morphine found in rodents is of dietary origin (8, 9). Clear answers concerning the presence of morphine in animals have been obscured by inadequate experimentation and possible laboratory contamination with morphine. Only recently, several reports appeared using sterile human cell cultures and isolated organs, which added to a body of evidence that morphine indeed occurs in mammals and human cell cultures (10-12). To substantiate these findings, we made use of the fact that morphine is excreted in urine of humans (13-15) and rats (7). The presence of morphine in urine has been unequivocally demonstrated by mass spectrometry (15), but the origin of the excreted morphine has not yet been clarified. If these trace amounts of morphine in urine are formed de novo (and are not from dietary intake), a biosynthetic apparatus should be present in mammals that catalyzes this multistep pathway.The goal of this investigation is to demonstrate the de novo formation of benzylisoquinoline alkaloids, mainly of the morphinan type, in live rodents. Our experimental strategy involves administration of stable-...

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Section: Resultsmentioning

confidence: 99%

Urinary excretion of morphine and biosynthetic precursors in mice

Grobe

Lamshöft

Orth³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Administration of L-DOPA results in the conversion of L-DOPA to dopamine (DA) in brain and leads to a replenishment DA in the surviving neurons. Tetrahydropapaveroline (THP; 6,7-dihydroxy-1-(3¢,4¢-dihydroxybenzyl)-1,2,3,4-tetrahydroisoquinoline), a metabolite of dopamine, has been detected in the urine of PD patients on L-DOPA medication [7][8][9], and in the brain and urine of rat treated with L-DOPA [10].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of DNA Damage and Apoptosis Induced by Tetrahydropapaveroline, a Metabolite of Dopamine

2006

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Tetrahydropapaveroline (THP), a metabolite of dopamine, has been suspected to be associated with dopaminergic neurotoxicity of L-DOPA. THP induced apoptosis in human leukemia cell line HL-60 cells, but did not in its hydrogen peroxide (H(2)O(2))-resistant clone HP100. THP-induced DNA ladder formation in HL-60 cells was inhibited by a metal chelator. THP induced damage to (32)P-labeled DNA fragments in the presence of metals. In the presence of Fe(III)EDTA, THP caused DNA damage at every nucleotide. The DNA damage was inhibited by free hydroxy radical ((.)OH) scavengers and catalase, suggesting that the Fe(III)EDTA-mediated DNA damage is mainly due to (.)OH generation. In the presence of Cu(II), THP caused DNA damage mainly at T and G of 5'-TG-3' sequence. The inhibitive effect of catalase and bathocuproine on Cu(II)-mediated DNA damage suggested that H(2)O(2) and Cu(I) participate in the DNA damage. This study demonstrated that THP-induced apoptosis via reactive oxygen species generated from reaction of H(2)O(2) and metals plays an important role in cytotoxicity of L-DOPA.

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“…However, it must be specified that the work supporting these suggestions has been performed on nonhuman or cellular systems. The presence of this compound is particularly evident in the plasma, urine, and brain of parkinsonian patients treated with L-dopa [2,3,7]. It has also been identified in the brain of rats treated with L-dopa [8].…”

Section: Introductionmentioning

confidence: 90%

Study on the ability of 1,2,3,4‐tetrahydropapaveroline to cause oxidative stress: Mechanisms and potential implications in relation to parkinson's disease

Soto‐Otero¹,

Sanmartín-Suárez²,

Sánchez-Iglesias³

et al. 2006

J Biochem & Molecular Tox

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Tetrahydropapaveroline (THP) is a compound derived from dopamine monoamine oxidase-mediated metabolism, particularly present in the brain of parkinsonian patients receiving L-dopa therapy, and is capable of causing dopaminergic neurodegeneration. The aim of this work was to evaluate the potential of THP to cause oxidative stress on mitochondrial preparations and to gain insight into the molecular mechanisms responsible for its neurotoxicity. Our data show that THP autoxidation occurs with a continuous generation of hydroxyl radicals (*OH) and without the involvement of the Fenton reaction. The presence of ascorbate enhances this process by establishing a redox cycle, which regenerates THP from its quinolic forms. It has been shown that the production of *OH is not affected by the presence of either ferrous or ferric iron. Although THP does not affect lipid peroxidation, it is capable of reducing the high levels of thiobarbituric acid-reactive substances obtained in the presence of ascorbate and/or iron. However, THP autoxidation in the presence of ascorbate causes both an increase in protein carbonyl content and a reduction in protein-free thiol content. THP also increases protein carbonyl content when the autoxidation occurs in the presence of iron. The remarkable role played by ascorbate in the production of oxidative stress by THP autoxidation is of particular interest.

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Determination of tetrahydropapaveroline in the urine of Parkinsonian patients receiving l-dopa—carbidopa (Sinemet) therapy by high-performance liquid chromatography

Cited by 21 publications

References 13 publications

Urinary excretion of morphine and biosynthetic precursors in mice

Urinary excretion of morphine and biosynthetic precursors in mice

Mechanism of DNA Damage and Apoptosis Induced by Tetrahydropapaveroline, a Metabolite of Dopamine

Study on the ability of 1,2,3,4‐tetrahydropapaveroline to cause oxidative stress: Mechanisms and potential implications in relation to parkinson's disease

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