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A K Cho

Publications and source records attributed to A K Cho.

At least 19 recordsLinked to original sources
PubMed1996

Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion.

3,4-Methylenedioxymethamphetamine (MDMA) affects both dopamine and serotonin (5-HT) systems. One of its acute actions is to cause a reversible fall in steady-state brain 5-HT concentrations. To investigate the chemical basis of this acute effect, the brain levels of the parent compound and three major metabolites, 3,4- 3,4-methylenedioxyamphetamine (MDA), 3,4-dihydroxymethamphetamine (DHMA) and 6-hydroxy-3,4-methylenedioxymethamphetamine (6-OHMDMA), were monitored, together with 5-HT levels, over a period of 6 hr in male Sprague-Dawley (SD) rats. The temporal relationships between drug concentrations of both stereoisomers and depletions were evaluated first. There was no correlation between the concentrations of the compounds measured and the extent of 5-HT depletion. Brain levels of MDMA and MDA were higher than plasma levels and exhibited a stereoselectivity in that (-)-MDMA and (+)-MDA levels were higher than those of enantiomers. The relationship between the dose of ((+)-MDMA and reduction in 5-HT levels was next investigated in SD male, SD female, and Dark Agouti (DA) female rats. These animals exhibit different capabilities of MDMA metabolism. There is a lower level of MDA, the N-demethylated metabolite of MDMA, in female SD rats than in males. Female DA rats are deficient in CYP2D isozymes, one of the enzymes responsible for demethylenation of MDMA to DHMA at pharmacological concentrations of substrate. there was a significant accuulation of MDMA in the brain and plasma of DA rats, but their 5-HT depletion was somewhat attenuated. The results indicated that MDMA ++ was apparently not the single, causative agent for the acute 5-HT depletion, which may also involve a metabolite formed by CYP2D.

3,4-Methylenedioxyamphetamine↗
PubMed1996

Selective mechanism-based inactivation of rat CYP2D by 4-allyloxymethamphetamine.

The high selectivity of amphetamine and its derivatives for CYP2D-mediated oxidations suggested the use of the phenylisopropylamine skeleton as a template for a selective inhibitor of this important enzyme. Accordingly, 4-allyloxymethamphetamine-amine (ALLMA) was synthesized and its ability to selectively inactivate CYP2D was investigated both in in vitro and in vivo experiments. Incubation studies with rat liver microsomes demonstrated that this compound suppressed the CYP2D-mediated methylenedioxymethamphetamine (MDMA) demethylation in time- and dose-dependent manner and that the inhibition required the presence of NADPH. The development of irreversible inhibition was associated with oxidation at position 4 of the aromatic ring, the common site of CYP2D-mediated oxidation of this group of compounds. In in vivo studies doses of ALLMA (1-10 mg/kg) were administered to adult male Sprague-Dawley rats and liver microsomes were obtained 3 hr later. Methamphetamine p-hydroxylation and low Km MDMA demethylation activities, both mediated by CYP2D, were reduced by more than 80% after a dose of 10 mg/kg. Cytochrome P-450 reactions attributed to P-450s other than CYP2D, such as aniline p-hydroxylation, the high Km system of MDMA demethylation and the N-demethylation of methamphetamine, benzphetamine, aminopyrine and erythromycin, all appeared to be minimally affected. The importance of aromatic ring oxidation in the metabolism is such that inhibition of CYP2D would be expected to cause a significant change in the pharmacokinetics of these compounds. The kinetics of MDMA metabolic activity in microsomes from ALLMA-pretreated rats were comparable to those from female Dark-Agouti rats, an animal model for CYP2D1 deficiency.

Animals↗
PubMed1995

Cytochrome P4502D isozymes catalyze the 4-hydroxylation of methamphetamine enantiomers.

The 4-hydroxylation of S(+)- and R(-)-methamphetamine by rat liver microsomes was examined in Sprague-Dawley and Dark Agouti strains to determine the role of cytochrome P4502D (CYP2D) subfamily isozymes in catalyzing the reaction. In the study, anti-P450-BTL IgG, bufuralol, and quinine, a substrate and inhibitors of CYP2D isozymes, respectively, were found to block approximately 90% of the reaction as catalyzed by microsomes from Sprague-Dawley rats. Reconstituted systems of CYP2D isozymes purified from rat liver microsomes also mediated the reaction. These observations and the minimal activity found in microsomes from Dark Agouti rats support the notion that methamphetamine, like other phenylisopropylamine compounds, is oxidized on the 4-position of the aromatic ring by CYP2D isozymes.

Animals↗
PubMed1995

Pharmacokinetic and pharmacodynamic analysis of the actions of D-amphetamine and D-methamphetamine on the dopamine terminal.

To establish whether the actions of D-amphetamine (Amp) and D-methamphetamine (MeAmp) on the striatal dopamine system were equipotent, pharmacokinetic profiles of each drug were applied to an analysis of their respective induced dopamine efflux profiles. Amp or MeAmp (1 and 5 mg/kg i.v.) was administered to chloral hydrate-anesthetized rats; plasma and brain kinetics were then assessed from 5 to 60 min. Dose-dependent increases in Amp and MeAmp plasma levels resulted in proportional increases in striatum levels that were equivalent for both drugs; elimination rates also were similar and were characterized by a first-order decay process. After MeAmp administration, low levels of brain MeAmp metabolites were detected throughout the 1-hr time period; relative to MeAmp, Amp and p-hydroxy-MeAmp levels were less than 10 and 1%, respectively. The drug-induced dopamine efflux profiles in the striatum were characterized by microdialysis; Amp and MeAmp (1, 2.5 and 5 mg/kg i.v.) effected equivalent, dose-dependent increases in extracellular dopamine levels. For both drugs at 5- and 10-min postinjection, increases in drug striatum levels preceded increases in dopamine efflux. In contrast, from the time of the peak dopamine responses observed at 10 to 20 min until the end of the study at 90 min, changes in striatal drug levels were correlated with extracellular dopamine levels; this correlation was similar for both drugs. These results indicate that Amp and MeAmp pharmacokinetics and their subsequent dopamine responses in the striatum are equivalent. The pharmacokinetic analysis can be extended to the interpretation of other comparative studies that assess effects of Amp and MeAmp.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Inactivation of constitutive hepatic cytochromes P450 by phencyclidine in the rat.

The purpose of this study was to determine whether phencyclidine (PCP) inhibits constitutive hepatic cytochrome P450 (CYP) isozymes when administered to naive adult male Sprague-Dawley rats. Animals were pretreated with PCP (25 mg/kg/day for 2 days), killed 3 and 16 hr after the last dose, and liver microsomes prepared. The washed microsomes were then assayed for benzphetamine, methamphetamine (MA), and methylenedioxymethamphetamine (MDMA) N-demethylation together with MDMA demethylenation and MA 4-hydroxylation activities. MDMA demethylenation (low substrate concentration), MA 4-hydroxylation, and metoprolol alpha-hydroxylation reactions, which are catalyzed by CYP2D isozymes, were reduced > 74% 3 hr after the last PCP dose and were only partially restored 13 hr later. Benzphetamine and (-)-MDMA N-demethylation activities were restored to control values 16 hr after the last dose. These results indicate that PCP suppresses constitutive isozymes, including CYP2C11 and members of the CYP2D subfamily. The suppression of cytochromes P450 activity by PCP in vivo is consistent with its in vitro actions found in this and other studies, and demonstrates that alteration of CYP activity is another pharmacological effect of this compound.

Amphetamines↗
PubMed1995

Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine.

Microdialysis in behaving animals was used to concomitantly characterize the dopamine and 5-HT responses in the caudate and the norepinephrine response in the hippocampus to the D- and L-isomers of amphetamine and methamphetamine. Doses of all four drugs which promoted similar stereotypy responses produced a D-amphetamine-like response profile of dopamine and dopamine metabolites, suggesting that all these drugs interact with dopamine systems to facilitate the release of transmitter. However, in contrast to the similar behavioral profiles, the magnitude of the dopamine responses diverged significantly. In addition, all four drugs increased extracellular norepinephrine and 5-HT, but the relative responses differed markedly from dopamine and from each other. The contrasting structure-activity relationships for these drugs likely reflect their differential potency at the various neuronal uptake transporters in promoting either transmitter release, and/or uptake blockade. In addition, the interaction of each drug at the vesicular transporters, as well as the availability of a cytoplasmic pool of transmitter likely also contribute to the neurotransmitter response. Because of the particularly divergent transmitter response profiles exhibited by L-methamphetamine, its behavioral and neurotransmitter effects were characterized over a more extended range of doses. Although the duration of the increase in extracellular dopamine was clearly proportional to dose, the dose-dependent increases in the magnitude of the dopamine response did not parallel the behavioral profiles. The results of these studies indicate that, while the dopamine, norepinephrine and 5-HT responses to these drugs probably contribute to the expression of stimulant-induced behaviors, simple relationships between the neurotransmitter responses and the behavioral profiles were not evident.

Amphetamine↗
PubMed1994

The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6).

The metabolism of methylenedioxymethamphetamine (MDMA, "ecstasy") was examined in a microsomal preparation of the yeast Saccharomyces cerevisiae expressing human debrisoquine hydroxylase, CYP2D6. Only one product, dihydroxymethylamphetamine (DHMA), was detected in the incubation mixture, and this product accounted for all of the substrate consumption at low concentration (10 microM). Mean +/- SD values of apparent Km(microM) and Vmax (nmol/min per nmol P450) for the demethylenation of (+) and (-)-MDMA at low concentrations (1-100 microM) were 1.72, 0.12 and 6.45, 0.10 and 2.90, 0.10 and 7.61, 0.06, respectively. At high concentrations (> 1000 microM) substrate inhibition was noted, with Ki values of 14.2 and 28.2 mM, respectively, for the (+) and (-) enantiomers. Incubation of MDMA isomers with human liver microsomes indicated that their demethylenation is deficient in the poor metabolizer phenotype. Thus, MDMA is converted to the catecholamine DHMA by CYP2D6, and this may give rise to genetically-determined differences in toxicity.

3,4-Methylenedioxyamphetamine↗
PubMed1994

Participation of cytochrome P450-2B and -2D isozymes in the demethylenation of methylenedioxymethamphetamine enantiomers by rats.

The cytochrome P450 isozymes in rat liver microsomes that catalyze the demethylenation of methylenedioxymethamphetamine enantiomers to the corresponding dihydroxymethamphetamine were characterized. Dihydroxymethamphetamine formation in liver microsomes from male Sprague-Dawley rats exhibited multienzyme kinetics, with Km values in the micromolar/millimolar range. The stereoselectivity [(+)-isomer versus (-)-isomer] varied from 0.78 to 1.94 after pretreatment of the rats with phenobarbital, 3-methylcholanthrene, pregnenolone-16 alpha-carbonitrile, or pyrazole, suggesting that different isozymes participate in the reaction. The low-Km demethylenation was not induced by these compounds and was not inhibited by antibodies raised against CYP2C11. Liver microsomes from female Dark-Agouti rats, a strain genetically deficient in CYP2D1, exhibited demethylenation activities that were 9% of those in microsomes from male Sprague-Dawley rats. The low-Km demethylenation was also inhibited by CYP2D substrates such as sparteine, bufuralol, or desipramine and was almost completely inhibited by antibodies against P450 BTL, which belongs to the CYP2D family. The higg-Km demethylation activity was induced by phenobarbital and pregnenolone-16 alpha-carbonitrile and the activity in both untreated and phenobarbital-induced microsomes was suppressed by anti-CYP2B1 IgG. Experiments with IgG raised against cytochrome b5 suggested that the hemoprotein contributed to the low-Km activity but not the high-Km activity. These results indicate that cytochrome P450 isozymes belonging to the CYP2D subfamily catalyze demethylenation with low Km values and that the reaction occurring with high Km values is likely to be mediated by members of the CYP2B family, but with the possible participation of other phenobarbital-inducible isoforms.

3,4-Methylenedioxyamphetamine↗
PubMed1993

A behavioral and pharmacokinetic study of the actions of phenylcyclohexyldiethylamine and its active metabolite, phenylcyclohexylethylamine.

Phenylcyclohexyldiethylamine (PCDE) is an analog of phencyclidine with low affinity for the N-methyl-d-aspartate receptor that is metabolized to an active monoethyl derivative, phenylcyclohexylethylamine (PCE). In a pharmacokinetic analysis of the ataxia response of rats to i.p. administered PCDE and PCE, ataxia intensity was determined together with plasma and cerebrospinal fluid concentrations of the drugs. The role of PCE as the active metabolite of PCDE was assessed quantitatively by correlating the response with both the plasma and cerebrospinal fluid drug levels. Increased PCE concentrations in the cerebrospinal fluid and plasma were associated with increased ataxia response when either PCDE or PCE was the administered drug. However, the concentration-response curves did not superimpose and the curve after PCDE was shifted to the left of that after PCE, suggesting that PCDE was contributing an effect not accountable by PCE concentration. This apparent potentiation must involve an interaction at sites other than the N-methyl-daspartate receptor. In the analysis of the behavior responses, PCDE was found to induce a greater backpedalling response which has been attributed to interaction with dopamine or serotonin systems, suggesting that other transmitter systems may contribute to the overall ataxia response.

Animals↗
PubMed1992

Aromatic hydroxylation of methylenedioxybenzene (MDB) and methylenedioxymethamphetamine (MDMA) by rabbit liver microsomes.

1. Metabolites formed during incubation of methylenedioxybenzene (MDB) and methylenedioxymethamphetamine (MDMA) with rabbit liver microsomes were examined by h.p.l.c.-electrochemical detection and g.l.c.-mass spectrometry. 2. The trifluoroacetyl derivative of metabolite M-1, obtained from MDB, had a molecular ion at m/z 234 and was identified as 3,4-methylenedioxy-6-hydroxybenzene (sesamol) by comparison with authentic material. 3. The trifluoroacetyl derivative of metabolite M-2, obtained from MDMA, exhibited a molecular ion at m/z 401. Experiments with the deuterium substituted variants of MDMA indicated that the product was hydroxylated on the aromatic ring. 4. The formation of these hydroxylated metabolites required NADPH and was inhibited by carbon monoxide, indicating the possible participation of cytochrome P-450. Phenobarbital (PB) induction caused a marked enhancement of MDP hydroxylase activity whereas MDMA hydroxylation was not affected. 5. The aromatic hydroxylation of MDB and MDMA was also observed in a reconstituted system with cytochrome P-450 isozyme IIB4.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Regiochemical differences in cytochrome P450 isozymes responsible for the oxidation of methylenedioxyphenyl groups by rabbit liver.

The cytochrome P450 isozymes catalyzing the oxidation of the methylenedioxyphenyl compounds methylenedioxybenzene (MDB) and methylenedioxyamphetamine (MDA) have been investigated in rabbit liver preparations. The aromatic ring in MDB undergoes both demethylenation to catechol and aromatic hydroxylation to sesamol, whereas that in MDA undergoes only demethylenation to dihydroxyamphetamine. Formation of catechol and sesamol from MDB in microsomal incubation mixtures was enhanced about 5- and 3-fold, respectively, by pretreatment of the rabbits with phenobarbital, which induced CYP2B4 and CYP4B1. The cytochrome P450 isozyme responsible for aromatic hydroxylation of MDB was induced by beta-naphthoflavone and was inhibited by alpha-naphthoflavone. Microsomal demethylenation of MDA was minimally sensitive to pretreatment of the rabbits with phenobarbital, beta-naphthoflavone, pyrazole, or rifampicin. However, MDA competitively inhibited the N-demethylation of erythromycin. Antibodies against CYP2B4, but not those against CYP4B1, caused a marked inhibition of the demethylenation and aromatic hydroxylation of MDB. Antibodies against CYP2C3 did not inhibit the demethylenation of MDA, nor did substrates or inhibitors of the CYP2D family except for bufuralol. MDB and MDA were both capable of forming metabolic intermediate complexes, and the rate of complex formation was accelerated by phenobarbital induction. Reconstitution experiments with CYP2B4 suggested that phenobarbital-inducible complex formation from MDA was not due to the carbene pathway involving the methylenedioxy group but was due to oxidation of the amino group. These results indicate that CYP2B4 oxidizes different regions of methylenedioxyphenyl compounds depending on their structure. MDB undergoes oxidation at the methylenedioxy group (major) and the benzene ring (minor). MDA is oxidized at the alkylamino side chain at the nitrogen and alpha-carbon. The results suggested that one or more constitutive isoforms (probably unknown) of cytochrome P450 present in rabbit liver microsomes are primarily responsible for MDA demethylenation but that CYP3A6 contributes slightly.

3,4-Methylenedioxyamphetamine↗
PubMed1992

Effects of xylamine on vascular neuroeffector transmission.

The effect of xylamine on sympathetic neuroeffector transmission in rabbit isolated blood vessels was examined. Xylamine (10(-8) to 10(-6) M) caused a slowly progressing inhibition of the contractions of pulmonary artery evoked by electrical field stimulation. The inhibition was irreversible. Cocaine (3 x 10(-5) M) prevented the inhibitory action of xylamine (10(-7) M), but it did not reverse the inhibition caused by xylamine (10(-6) M). Xylamine (10(-7) to 3 x 10(-5) M) reduced the accumulation of [3H]norepinephrine (NE) (10(-8) M). In the presence of desipramine (10(-6) M), xylamine (10(-7) to 3 x 10(-5) M) and corticosterone (10(-6) to 10(-4)) reduced the 3H-accumulation. Xylamine (10(-7) to 10(-5) M) reduced the tissue NE content by up to 50%. Xylamine (10(-7) to 10(-6) M) antagonized in a noncompetitive manner the contractions of aorta evoked by NE (10(-9) to 3 x 10(-5) M), histamine (10(-6) to 3 x 10(-4) M) and 5-hydroxytryptamine (10(-8) to 3 x 10(-4) M). In the case of NE, the antagonism was more marked in the presence of either cocaine (3 x 10(-5) M) plus corticosterone (4 x 10(-5) M) or corticosterone (4 x 10(-5) M). In the presence of xylamine (10(-7) to 10(-6) M), cumulative addition of near maximally effective concentrations of NE, 5-hydroxytryptamine and histamine caused a progressive and complete relaxation of aorta. Xylamine (10(-7) to 10(-5) M) did not alter the contractions of aorta evoked by potassium (17-55 mM). The results support the contention that xylamine is an inhibitor of neuronal and extraneuronal uptake, an adrenergic neurone blocking agent and a noncompetitive antagonist of alpha-1 adrenoceptors, histamine and 5-hydroxytryptamine2 receptors. Xylamine is not a direct acting vasodilator on smooth muscle.

Animals↗
PubMed1991

A pharmacokinetic analysis of 3,4-methylenedioxymethamphetamine effects on monoamine concentrations in brain dialysates.

Interpretation of the in vivo actions of 3,4-methylenedioxymethamphetamine (MDMA) is complicated by the formation of the active metabolite, 3,4-methylenedioxyamphetamine (MDA). This study evaluates the role of MDA in the dopamine releasing actions of (+)-MDMA. In the study, rats were given subcutaneous doses of (+)-MDMA and concentrations of monoamines and their metabolites in striatal dialysate were measured at 15 min intervals. In parallel experiments, plasma concentrations of (+)- and (-)-MDMA and MDA were determined by GC/MS procedures. The time course of MDMA levels was comparable for the two isomers as were their bioavailabilities. In contrast, the plasma levels of MDA were about three times higher after (+)-MDMA. (+)-MDMA caused a rapid increase in striatal dialysate levels of dopamine and decreased extracellular levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). There was a significant correlation between dopamine concentration in striatal dialysate and plasma MDMA concentration, but not with plasma MDA. These results indicate that MDMA itself has stereoselective actions on dopamine neurons. However, the higher plasma MDA levels after (+)-MDMA may account for part of the enantiomeric differences in the behavioral and neurotoxicological effects of MDMA.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Metabolism of methylenedioxyphenyl compounds by rabbit liver preparations. Participation of different cytochrome P450 isozymes in the demethylenation reaction.

The cytochrome P450-mediated oxidative demethylenation of the benzo-1,3-dioxoles (methylenedioxyphenyl compounds, MDPs), methylenedioxybenzene (MDB), methylenedioxyamphetamine (MDA), and methylenedioxymethamphetamine (MDMA), by rabbit liver microsomes and cytochrome P450IIB4 (CYP2B4) was examined. Material balance studies indicated that demethylenation to catechol derivatives is a major metabolic pathway for MDB, MDA and MDMA. The reactions required NADPH and were inhibited by CO/O2 (4:1, v/v). Biphasic double-reciprocal plots of MDMA, MDA and MDB oxidation suggested participation of more than one isozyme of cytochrome P450 in the reaction. Phenobarbital (PB) induction was selective in that the Vmax values for MDB were increased but not those for MDA and MDMA. Exposure of liver microsomes from PB-pretreated animals to phencyclidine (PCP) markedly suppressed MDB oxidation but had little effect on MDA and MDMA demethylenation. Reconstitution experiments with CYP2B4 demonstrated that MDB is a good substrate for the isozyme; but the relative demethylenation activities for MDA and MDMA were 1 and 2% of that for MDB. These results indicate that the PB-inducible isozymes such as CYP2B4 appear to play an important role in MDB demethylenation, whereas MDA and MDMA oxidation is mediated mainly by constitutive isozymes.

3,4-Methylenedioxyamphetamine↗
PubMed1991

Pharmacokinetic and pharmacodynamic properties of some phencyclidine analogs in rats.

The pharmacodynamics and pharmacokinetics of three phencyclidine analogs, differing from phencyclidine (PCP) only in the nature of the amine structure, were determined after intravenous doses of equimolar amounts to rats. The purpose of the study was to assess the role of pharmacokinetics in the in vivo potency of the compounds. The compounds examined were phenylcyclohexyl-pyrrolidine (PCPY), diethylamine (PCDE), ethylamine (PCE), and phencyclohexylamine (PCA). The behavior responses monitored included ataxia and others previously shown to be characteristic of PCP. In contrast to their relative affinities for the MK 801 binding site, the behavioral potencies of PCE, PCDE and PCPY were comparable to PCP. The major discrepancy occurred with PCDE, whose affinity for the NMDA receptor was 1/20th of PCP. The pharmacokinetic studies showed that the discrepancy between in vivo and in vitro activity of PCDE could be partially accounted for by its conversion to PCE, a relatively potent PCP-like agent.

Animals↗
PubMed1991

Determination of the mechanism of demethylenation of (methylenedioxy)phenyl compounds by cytochrome P450 using deuterium isotope effects.

The mechanism of demethylenation of (methylenedioxy)benzene (MDB), (methylenedioxy)amphetamine (MDA), and (methylenedioxy)methamphetamine (MDMA) by purified rabbit liver cytochrome P450IIB4 has been investigated by using deuterium isotope effects. A comparison of the magnitude and direction of the observed kinetic isotope effects indicates that the three compounds are demethylenated by different mechanisms. The different mechanisms of demethylenation have been proposed on the basis of comparisons of the observed biochemical isotope effects with the isotope effects from purely chemical systems.

3,4-Methylenedioxyamphetamine↗
PubMed1990

MK-801 ameliorates delayed amnesia, but potentiates acute amnesia induced by CO.

The effects of non-competitive N-methyl-D-aspartate receptor antagonists on amnesia induced by carbon monoxide (CO) were investigated, since they have neuroprotective effects on delayed degeneration induced by ischemia. In the mice exposed to CO, acute and delayed amnesia were induced. (+)-MK-801 and (-)-MK-801 improved the delayed amnesia, but the effects of phencyclidine (PCP) were weak. (+)-MK-801 and PCP potentiated the acute amnesia. From these results, it is suggested that there is a stereoselectivity in the effects of MK-801 on CO-induced amnesia and that CO-induced delayed amnesia animals could be used as an ischemic amnesia model.

Amnesia↗