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Biomedical subjects

A J Trevor

Publications and source records attributed to A J Trevor.

At least 19 recordsLinked to original sources
PubMed1990

In vivo intracerebral microdialysis studies in rats of MPP+ analogues and related charged species.

The in vivo dopaminergic neurotoxic properties of 45 MPTP and MPP+ analogues and related compounds were examined by an intrastriatal microdialysis assay in conscious rats. MPP(+)-like toxicity, as evidenced by the irreversible effects on DA release and enhancement of lactate formation, was observed with a variety of structural types although no compound was more toxic than MPP+. The following global structure-toxicity relationships could be derived: (1) only permanently charged compounds showed neurotoxic effects; (2) with the exception of amino groups, hydrophilic substituents abolished toxicity; (3) activity was enhanced by lipophilic groups although increased steric bulk around the nitrogen atom tended to decrease activity; (4) nonaromatic, quaternary systems (methiodide of MPTP, guanidinium derivatives) were only weakly toxic; and (5) certain bi- and tricyclic systems, including putative metabolites of potential endogenous MPTP-like compounds, were weakly toxic. The lack of toxic effects following perfusions with DA itself confirmed that MPTP dopaminergic neurotoxicity is not likely to be mediated by the MPP(+)-induced release of DA. With some interesting exceptions, these in vivo data correlate reasonably well with in vitro data on the nerve terminal uptake properties and the inhibitory effects on mitochondrial respiration of these compounds.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

1-methyl-4-phenylpyridinium (MPP+) analogs: in vivo neurotoxicity and inhibition of striatal synaptosomal dopamine uptake.

The ability of various 1-methyl-4-phenylpyridinium (MPP+) analogs to inhibit the uptake of tritium labeled dopamine and MPP+ by synaptosomes prepared from neostriata of male C57 Black mice was measured and compared with their dopaminergic neurotoxic potential which was estimated by an in vivo intracerebral microdialysis technique. The correlation observed between these two properties suggests that nerve terminal uptake is an important step in the expression of the nigrostriatal toxicity of structural analogs of MPP+. The uptake inhibition and neurotoxic properties of this series of compounds appear to be highly structurally sensitive and suggest that few nitrogenous bases will be potent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-type neurotoxins.

1-Methyl-4-phenylpyridinium↗
PubMed1988

The formation of reactive intermediates in the MAO-catalyzed oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

Oxidation of MPTP by monoamine oxidase (MAO), leading to the formation of reactive metabolites, is a critical step in the expression of the nigrostriatal toxicity of this molecule. A catalytic mechanism for the 2-electron oxidation of MPTP to MPDP+ and for the further 2-electron oxidation of MPDP+ to MPP+ is proposed, involving the formation of carbon-centered radical intermediates. These radical species appear to be involved in the mechanism-based inactivation of MAO by MPTP, possibly by generating 1,4-dihydropyridine adducts with the enzyme apoprotein or its coenzyme FAD. The pathways of metabolism of MPTP in brain and peripheral tissues and the active accumulation of metabolites of MPTP in dopaminergic neurons are discussed in terms of their possible contribution to the selective cytotoxicity of the compound.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

Effect of etomidate on hepatic drug metabolism in humans.

The authors studied the effect of etomidate on drug metabolism in vivo in humans and in vitro using human liver microsomes. When these liver microsomes were incubated with different concentrations of etomidate, dose-dependent inhibition of ketamine N-demethylation, a cytochrome P-450-dependent enzymatic process, was produced. Cytochrome P-450 binding spectra displayed type II binding with a UV light absorption maximum (lambda max) at a wavelength of 424 nm in the presence of etomidate. In vivo studies were conducted using ketamine and antipyrine as substrates. Evaluation of antipyrine's pharmacokinetic variables after an intravenous infusion of etomidate (0.34 +/- 0.17 mg/kg) revealed an 18% increase in its elimination half-life (P = 0.04). In addition, there were 16% and 11% decreases in the area under the curve (P = 0.05) and in the clearance rate (P = 0.07) for antipyrine, respectively. In patients administered a bolus dose of ketamine during brief outpatient operations, etomidate produced no significant changes in ketamine's pharmacokinetics compared to thiopental. The authors conclude that the etomidate-induced inhibition of hepatic drug metabolism can prolong the elimination of drugs with low hepatic clearance rates (e.g., antipyrine). However, etomidate would not be expected to alter the rate of elimination of high clearance anesthetics and analgesic drugs (e.g., ketamine, fentanyl).

Antipyrine↗
PubMed1987

Cation-exchange high-performance liquid chromatography assay for the nigrostriatal toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its monoamine oxidase B generated metabolites in brain tissues.

This paper describes a sensitive (1 pmol/mg tissue) and selective bioanalytical method for the quantitative estimation of the nigrostriatal toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its monoamine oxidase B generated metabolites, the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+ and the 1-methyl-4-phenylpyridinium species MPP+. The method is based on initial separation of the analytes after treatment of brain tissue homogenates with 5% trichloroacetic acid. The soluble fraction is analyzed directly by cation-exchange high-performance liquid chromatography employing a diode array UV detector. Results obtained with this assay have provided the first evidence for the presence of MPDP+ in the mouse brain following intravenous administration of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Bioactivation of MPTP: reactive metabolites and possible biochemical sequelae.

Expression of the selective nigrostriatal neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] requires its bioactivation by MAO B which leads to the formation of potentially reactive metabolites including the 2-electron oxidation product, 1-methyl-4-phenyl-2,3-dihydropyridinium species [MPDP+] and the 4-electron oxidation product, the 1-methyl-4-phenyl pyridinium species [MPP+]. The latter metabolite accumulates in brain striatal tissues, is a substrate for dopaminergic active uptake systems and is an inhibitor of mitochondrial NADH dehydrogenase, a respiratory chain enzyme located in the inner mitochondrial membrane. In intact mitochondria this inhibition of respiration may be facilitated by active uptake of MPP+, a process dependent on the membrane electrical gradient. In considering possible mechanisms involved in the biochemical effects of MPP+, its redox cycling potential appears to be much lower than its chemical congener paraquat, based on attempted radical formation by chemical or enzymic reduction. Theoretically, a carbon-centered radical intermediate could be formed by 1-electron reduction of MPP+, or by 1-electron oxidation of 1-methyl-4-phenyl-1,2-dihydropyridine, the free base form of MPDP+. The 1-electron reduction of such a radical could form 1-methyl-4-phenyl-1,4-dihydropyridine [DHP]. Synthetic DHP is neurotoxic in C57B mice, and its administration leads to the formation of MPP+ in the brain, presumably through rapid auto-oxidation. The hydrolysis of DHP would yield 3-phenylglutaraldehyde and methylamine. Recent studies demonstrating the formation of methylamine in brain mitochondrial preparations containing MPTP support our suggestion that DHP may be a brain metabolite of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Processing of MPTP by monoamine oxidases: implications for molecular toxicology.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), a selective nigrostriatal neurotoxin, is bioactivated by MAO-B (and less effectively by MAO-A) to 2,3-MPDP+ and this intermediate undergoes further oxidation to MPP+, partly through the activity of MAO forms. MPTP and its two primary metabolites are competitive inhibitors of both A and B forms of MAO. MPTP and 2,3-MPDP+ are also mechanism-based inactivators of both forms of the enzyme. A catalytic mechanism, involving the formation of radical intermediates, is proposed for the MAO-mediated oxidation of MPTP. Post-oxidation biochemical sequelae, possibly involved in the expression of neurotoxicity, include the active accumulation of MPP+ via dopamine reuptake systems, the energy-driven uptake of MPP+ by mitochondria and the inhibition of NADH dehydrogenase by pyridine derivatives. A scheme linking these events as steps in the molecular mechanism of action of MPTP is proposed and discussed in terms of the selective toxicity of the neurotoxin towards nigrostriatal cells.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man.

The pharmacodynamics of a racemic mixture of ketamine R,S(+/-)-ketamine and of each enantiomer, S(+)-ketamine and R(-)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(-)-ketamine was not as effective as R,S(+/-)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean +/- SD) of the median frequency (Emax) for R(-)-ketamine was 4.4 +/- 0.5 Hz and was significantly different from R,S(+/-)-ketamine (7.6 +/- 1.7 Hz) and S(+)-ketamine (8.3 +/- 1.9 Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8 +/- 0.5 micrograms/mL for R(-)-ketamine; 2.0 +/- 0.5 micrograms/mL for R,S(+/-)-ketamine; and 0.8 +/- 0.4 microgram/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(-)-ketamine was different from that of S(+)-ketamine and R,S(+/-)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.

Adult↗
PubMed1987

Role of 1-methyl-4-phenylpyridinium ion formation and accumulation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity to isolated hepatocytes.

The parkinsonian-inducing compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is converted by isolated hepatocytes to its primary metabolite, the 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+), and to its fully oxidized derivative, 1-methyl-4-phenylpyridinium ion (MPP+). Only the latter, however, accumulates in the cells. Incubation of hepatocytes in the presence of MPDP+ also results in the selective intracellular accumulation of MPP+. Conversion to MPP+ is more rapid and extensive after exposure to MPDP+, than with MPTP and the former is also more toxic. Addition of MPP+ itself is toxic to hepatocytes but only after a long lag period, which presumably reflects its limited access to the cell and its relatively slow intracellular accumulation. As previously shown with MPTP and MPP+, the cytotoxicity of MPDP+ is dose-dependent and is consistently preceeded by complete depletion of intracellular ATP. Similar to MPP+ but not MPTP, MPDP+ causes a comparable rate and extent of cytotoxicity and ATP loss in hepatocytes pretreated with the monoamine oxidase inhibitor pargyline. Pargyline blocks hepatocyte biotransformation of MPTP to MPP+, but it has no significant effect on MPP+ accumulation after exposure to either MPDP+ or MPP+. It is concluded that MPTP is toxic to hepatocytes via its monoamine oxidase-dependent metabolism and that MPP+ is likely to be the ultimate toxic metabolite which accumulates in the cell, causing ATP depletion and eventual cell death.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Interactions of the 1-methyl-4-phenyl-2,3-dihydropyridinium species with synthetic dopamine-melanin.

This paper describes interactions between the 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) metabolite of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) with synthetic dopamine-melanin, a polymeric pigment which is similar to the neuromelanin found in the nigrostriatal cell bodies of humans and primates. Although MPTP and its 1-methyl-4-phenylpyridinium (MPP+) metabolite bind to the synthetic pigment at physiological pH, both compounds are recovered quantitatively upon treatment with acid. Unlike MPTP and MPP+, MPDP+ proved to be unstable in the presence of synthetic dopamine-melanin which promoted its conversion to the fully oxidized pyridinium product MPP+. The possible biological significance of this interaction is discussed.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes.

Mouse brain synaptosomal preparations were used to study uptake of N-methyl-4-phenylpyridine (MPP+), a metabolite of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The uptake of [3H]-MPP+ by striatal synaptosomes was approximately 25 X greater than that of [3H]-MPTP, with a KM of 0.48 microM and a Vmax of 5.3 nmoles/g tissue/min. Uptake was Na+ dependent and inhibited by ouabain, cocaine and dopamine (Ki 0.12 microM). Synaptosomes prepared from the corpus striatum accumulated [3H]-MPP+ at a rate 5-10 times higher than preparations from other brain regions. This selective uptake of MPP+ may contribute to the specificity of the toxic effects of MPTP on nigrostriatal dopaminergic neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Potential bioactivation pathways for the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

The metabolism of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied in rat brain mitochondrial incubation mixtures. The 1-methyl-4-phenylpyridinium species MPP+ has been characterized by chemical ionization mass spectral and 1H NMR analysis. Evidence also was obtained for the formation of an intermediate product which, with the aid of deuterium incorporation studies, was tentatively identified as the alpha-carbon oxidation product, the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+. Comparison of the diode array UV spectrum of this metabolite with that of the synthetic perchlorate salt of MPDP+ confirmed this assignment. The oxidation of MPTP to MPDP+ but not of MPDP+ to MPP+ is completely inhibited by 10(-7) M pargyline. MPDP+, on the other hand, is unstable and rapidly undergoes disproportionation to MPTP and MPP+. Based on these results, we speculate that the neurotoxicity of MPTP is mediated by its intraneuronal oxidation to MPDP+, a reaction which appears to be catalyzed by MAO. The interactions of MPDP+ and/or MPP+ with dopamine, a readily oxidizable compound present in high concentration in the nigrostriatum, to form neurotoxic species may account for the selective toxic properties of the parent drug.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Comparative pharmacology of the ketamine isomers. Studies in volunteers.

The clinical and electroencephalographic (EEG) effects of the individual ketamine isomers were compared with the racemic mixture in five volunteers who received each drug on a separate occasion. Racemic ketamine 275 +/- 25 mg, s(+) ketamine 140 +/- 21 mg or R(-) ketamine 429 +/- 37 mg produced an anaesthetic state lasting 6 +/- 2 min (mean +/- SD). However, the EEG evaluation of the R(-) isomer revealed less overall slowing, and an absence of the large slow wave complexes produced by the S(+) isomer and the racemic mixture. The pharmacokinetic profiles for the individual isomers of ketamine did not differ significantly from the racemic mixture. Even though the apparent anaesthetic state produced in these healthy volunteers did not differ qualitatively between the three drug groups, recovery times (assessed using a standardized battery of psychometric tests) were consistently shorter following the individual isomers compared with the racemic mixture. The serum ketamine concentrations associated with regaining consciousness and orientation were consistent with an S(+):R(-) isomer potency ratio of 4:1. In terms of their ability to impair psychomotor function, the S(+):R(-) potency ratio varied from 3:1 to 5:1. After comparable degrees of CNS depression, we conclude that the more potent S(+) isomer of ketamine was associated with a more rapid recovery of psychomotor skills than the currently used racemic mixture.

Adult↗
PubMed1982

Lipid-protein interactions as determinants of activation or inhibition by cytochrome b5 of cytochrome P-450-mediated oxidations.

Activation or inhibition by cytochrome b5 of benzphetamine N-demethylation was studied in micelle-reconstituted systems containing cytochrome P-450 LM2, NADPH-cytochrome P-450 reductase, and dilauroyl-phosphatidylcholine. The effects of cytochrome b5 were critically dependent on both protein:protein and lipid:protein ratios. A 200% stimulation of N-demethylation by cytochrome b5 was obtained at cytochrome P-450 reductase:cytochrome P-450 ratios similar to those in microsomes, compared to only a 20% stimulation at a ratio of 1:1. At lipid:protein ratios less than 50:1, the addition of cytochrome b5 caused significant inhibition of benzphetamine N-demethylation. Such an inhibition could be partially reversed by increasing phospholipid content of micelles and was not seen in vesicle-reconstituted systems at cytochrome b5:cytochrome P-450 ratios of 1:1 or lower. At high cytochrome P-450 reductase:cytochrome P-450 ratios, addition of cytochrome b5 did not alter the efficiency (80%) with which NADPH was utilized: however, at ratios similar to those in microsomes, an increase in efficiency from 42% to 80% was observed. The function of cytochrome b5 was interpreted in terms of a model in which inhibition of cytochrome P-450-mediated reactions results from changes in phospholipid-protein interactions and activation occurs via facilitation of electron transfer between NADPH-cytochrome P-450 reductase and cytochrome P-450 in the membrane.

Animals↗