Detection of Morphinone as a New Metabolite of Morphine in Guinea Pig Urine

Ishida, Takashi; Yamano, Shigeru; Toki, Satoshi

doi:10.1016/b978-0-444-80402-0.50161-3

Cited by 9 publications

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“…MO-GSH was purified from the bile after extensive chromatography, and the structure of the metabolite was analyzed by FABMS (MH + = 591) and NMR spectrometry. Interestingly, twodimensional NMR spectrometry (COSY and HETCOR) confirmed that the GSH residue preferentially attacks C-8 from the upper (less sterically hindered) side of the molecule, forming the 8S isomer(66). A similar stereochemical picture is observed with the related metabolite codeinone-GSH, an oxidation product of codeine, which has been detected in the bile of codeine-treated guinea pigs (100).…”

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confidence: 83%

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Glutathione conjugation of a cocaine pyrolysis product AEME and related compounds

Myers¹

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Free-base ("crack") cocaine smoking continues to be a popular method of drug abuse in the United States. Pyrolysis of free-base cocaine readily occurs, forming primarily benzoic acid and anhydroecgonine methyl ester (AEME), which structurally contains an α,βunsaturated carbonyl functional group. This electrophilic structure is suggestive of chemical reactivity with ubiquitously occurring cellular nucleophiles, such as glutathione. Glutathione adducts formed in vivo are metabolized to N-acetylcysteine derivatives by the enzymatically driven mercapturic acid pathway. AEME and its transesterification product in the presence of ethanol, anhydroecgonine ethyl ester (AEEE), were synthesized from cocaine hydrochloride. Glutathione (GSH) and mercapturic acid (NAC) conjugates of AEME were synthesized, and the stereochemistry of the AEME-NAC conjugate was structurally elucidated by NMR and mass spectrometry. Using Ellman's method to monitor glutathione depletion over time, AEME reacted with GSH at a slower rate (6.8 x 10-3 mM-1 min-1) than equimolar concentrations of arecoline or ethacrynic acid (2.2 × 10-1 mM-1 min-1 and 4.1 × 10-1 mM-1 min-1 , respectively). AEME also reduced the chemical formation of the DCNB-SG conjugate. In pooled human liver cytosol, the incubation of AEME with GSH at 37°C for 60 minutes at different pH levels was analyzed by LC-MS. We found unequivocal data suggesting enzymatic catalysis of AEME to AEME-SG in the presence of reduced GSH. However, AEME (10 mM) significantly reduced GST activity (p < 0.005) following a 20 hour incubation with HLC (1 mg). Additionally, AEME exhibited mixed-linear inhibition (K i = 334 µM) towards cytosolic GST activity. A solid phase extraction (SPE) method was developed to extract cocaine and cocaine metabolites from urine. We identified approximately 50 ng/mL of AEEE by LC-MS in the urine of a known freebase cocaine/ethanol abuser, and additionally confirmed the structure of the metabolite by LC-MS/MS. This SPE method is useful in detecting AEME conjugates in biological fluids. We studied the cytotoxicity of pyrolysis products on A549 lung fibroblasts using trypan blue exclusion and flow cytometry. To summarize, our work suggests that AEME plays a potential role in the sequelae of abused cocaine related toxicities.

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confidence: 83%

“…MO), containing an α,β-unsaturated ketone, is the oxidation product of the opiate analgesic morphine in the presence of morphine dehydrogenase(66). MO reacts readily with the thiol containing compounds 2-mercaptoethanol, cysteine and glutathione by a 1,4 Michael addition reaction(99).…”

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Glutathione conjugation of a cocaine pyrolysis product AEME and related compounds

Myers¹

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“…The remainder of the Figure compares the nonenzymatic vs. enzymatic GSH conjugation of five xenobiotics; the reactions were monitored spectrophotometrically and involved a 1-min incubation of the xenobiotic with GSH in the absence of enzymes, followed by the addition of an aliquot of rat liver cytosol and a further 1-min incubation [280a]. We begin with morphinone (4.435), a rather unstable metabolite of morphine produced by dehydrogenation of its secondary alcohol group [305]. 1,2-Dichloro-4-nitrobenzene (4.388) was a fair GST substrate and reacted spontaneously with GSH.…”

Section: Figs 499 and 4100mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 4. Reactions of Conjugation and Their Enzymes

Testa

Kraemer

2009

ChemInform

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This Part 4 of our biochemical introduction to drug metabolism [1 -4] presents the reactions of conjugation and their enzymes. As we shall see, reactions of conjugation are also a major focus of interest in the metabolism of drugs and other xenobiotics. Books specifically dedicated to conjugation reactions are rare [5], but much recent information can be found in book chapters (e.g.,For a reaction of conjugation to occur, a suitable functional group must be present in the substrate, which will serve as the anchoring site for an endogenous molecule or moiety such as CH 3 , sulfate, glucuronic acid, or glutathione. Conjugation reactions are thus synthetic (i.e., anabolic) reactions whose products are of modestly to markedly higher molecular weight than the corresponding substrate. As for the anchoring group, it can either be present in a xenobiotic or be created by a functionalization reaction. In other words, reactions of conjugation are able to produce first-generation as well as later-generation metabolites. We, therefore, consider as unfelicitous the term of phase II reactions commonly used to designate conjugations.A first issue when discussing reactions of conjugation will be to offer a clear definition. As we shall see, a number of criteria exist, all of which show some degree of fuzziness, and only one of which must necessarily be met. This has indeed led to some confusion with reactions of hydrolysis, which some biochemists have viewed as conjugation. We oppose such a view for reasons previously explained [3]. To repeat what we stated, reactions of hydrolysis are not catalyzed by transferases (EC 2) but by hydrolases (EC 3) [8], and water is not an endogenously synthesized molecule or moiety linked covalently to a cofactor.Reactions of conjugation, like the reactions of functionalization we saw in Parts 2 and 3, act on exogenous substrates (i.e., xenobiotics [1]) as well as endogenous substrates (i.e., endobiotics). This dual functionality may create a potential for metabolic interaction between a drug and an endogenous substrate, a frequently overlooked mechanism of toxicity. Thus, there may be competitive affinity for the catalytic site of an endobiotic-metabolizing enzyme, or there may be competition for the limited supply of a cofactor. A typical example of the latter case is found with

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“…Subsequently, Yamano et al (8) purified and characterized an NAD(P)-dependent dehydrogenase (M6DH) catalyzing oxidation of morphine to morphinone from guinea-pig liver cytosol. Kumagai et al developed a method for simultaneous determination of morphinone and its related metabolites of morphine by highperformance liquid chromatography (9), and isolated an unidentified metabolite from the bile of guinea-pig administered morphine (10,11). The isolated metabolite was identified as (8S)-(glutathion-Syl)dihydromorphinone in comparison with the synthetic morphinone-GSH adduct.…”

Section: Covalent Attachmentmentioning

confidence: 99%

Possible mechanisms for induction of oxidative stress and suppression of systemic nitric oxide production caused by exposure to environmental chemicals

Kumagai

Shimojo

2002

Environ Health Prev Med

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The cytotoxic effects evoked by exposure to environmental chemicals having electrophilic properties are often attributable to covalent attachment to intracellular macromolecules through sulfhydryl groups or enzyme-mediated redox cycling, leading to the generation of reactive oxygen species (ROS). When huge amounts of ROS form they overwhelm antioxidant defenses resulting in the induction of oxidative stress. Nitric oxide (NO) which plays a crucial role in vascular tone, is formed by endothelial NO synthase (eNOS). Since a decrease in systemic NO production is implicated in the pathophysiological actions of vascular diseases, dysfunction of eNOS by environmental chemicals is associated with cardiopulmonary-related diseases and mortality. In this review, we introduce the mechanism-based toxicities (covalent attachment and redox cycling) of electrophiles. Therefore, this review will focus on the possible mechanisms for the induction of oxidative stress and impairment of NO production caused by environmental chemicals.

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Detection of Morphinone as a New Metabolite of Morphine in Guinea Pig Urine

Cited by 9 publications

References 1 publication

Glutathione conjugation of a cocaine pyrolysis product AEME and related compounds

Glutathione conjugation of a cocaine pyrolysis product AEME and related compounds

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 4. Reactions of Conjugation and Their Enzymes

Possible mechanisms for induction of oxidative stress and suppression of systemic nitric oxide production caused by exposure to environmental chemicals

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