A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro.

Riley, RJ; Lambert, Claude; Kitteringham, Neil R.; Park, B K

doi:10.1111/j.1365-2125.1989.tb03445.x

Cited by 14 publications

(5 citation statements)

References 28 publications

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“…Circumstantial evidence has been presented, which links toxicity to the P450-mediated bioactivation of the parent compound 97 and its primary urinary metabolites , 8-hydroxymianserin ( 98 ), and N -desmethyl-mianserin ( 99 ) to the corresponding reactive iminium ions 100 – 102 in HLM (Scheme ). − The detection of cyanide adduct(s) , in incubations of 97 in HLM containing NADPH and cyanide is consistent with these observations. Studies with radiolabeled mianserin and its metabolites also resulted in the NADPH-dependent, irreversible incorporation of radiolabel in microsomal protein and cytotoxicity toward human mononuclear leukocytes included in the microsomal incubation. , A reactive iminium species 103 and its corresponding cyanide adduct 104 have also been detected in incubations of mianserin human neutrophils and in incubations with horseradish peroxidase/H 2 O 2 .…”

Section: Adverse Drug Reactions Linked To Iminium/aldehyde Formationsupporting

confidence: 79%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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Soft electrophiles (e.g., epoxides, quinones, quinone-imines, quinone-methides, etc.) generated via the oxidative bioactivation of phenyl, phenolic, amino-, and alkylphenolic substituents can be trapped with nucleophiles of comparable softness (e.g., glutathione or cysteine) in reactive metabolite screens. In contrast, hard nucleophiles such as cyanide and amines are frequently utilized to trap hard electrophiles (e.g., iminiums and aldehydes) that result from the oxidative bioactivation of cyclic (or acylic) amines and primary alcohols. In some instances, soft sulfydryl nucleophiles have also been utilized to trap aldehydes to yield cyclized thiazolidine adducts. Case studies where hard electrophiles are thought to be responsible for cytochrome P450 inactivation, genotoxicity, and/or target organ toxicity in animals have been presented. The association of hard electrophiles with immune-mediated idiosyncratic adverse drug reactions is less clear given the paucity of available examples and the fact that several marketed drugs containing cyclic amine motifs can generate hard electrophiles via α-carbon ring oxidation. This perspective examines available data associating toxicity with the formation of hard electrophilic intermediates from small molecule drugs/drug candidates. Pragmatic risk mitigation strategies around unwarranted idiosyncratic toxicity risks with drug candidates that generate hard electrophiles are also discussed against the backdrop of marketed agents that possess analogous cyclic amine framework.

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Section: Adverse Drug Reactions Linked To Iminium/aldehyde Formationsupporting

confidence: 79%

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Kalgutkar

2016

Chem. Res. Toxicol.

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“…1). However, in agreement with previous studies (Riley et al 1989), a stereochemical difference was observed with NADPH-dependent cytotoxicity being greater with (-)-mianserin than with (+)-mianserin ( Fig. 1); (+)mianserin, in contrast, showed direct cytotoxicity at high concentrations.…”

Section: Resultssupporting

confidence: 92%

Elucidation of the structural requirements for the bioactivation of mianserin in-vitro

Roberts

Kitteringham

Park

1993

Journal of Pharmacy and Pharmacology

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The aim of this study was to investigate structure-activity relationships among a series of compounds related to the antidepressant drug, mianserin, with respect to their ability to produce cytotoxic metabolites. Human peripheral lymphocytes were used as target cells and these were exposed to the individual compounds, in the presence or absence of a drug metabolizing system derived from human liver. The individual enantiomers of mianserin showed differences in their cytotoxicity profiles; the R-(-) isomer giving NADPH-dependent cytotoxicity while the S-(+) isomer showed direct cytotoxicity at high concentrations. Cytotoxicity was reduced by removal from mianserin of the nitrogen atom at the 5 position and by substitution of a methyl group for a hydrogen atom at position 14b. In contrast, insertion of an oxygen atom at position 10 of the drug molecule, precluding the formation of a carbonium ion, had little effect on cytotoxic metabolite formation. The data are consistent with the proposal that one or more iminium ions derived from mianserin are responsible for the cytotoxicity observed in this in-vitro system and that appropriate chemical modification may preclude bioactivation of mianserin by P450 enzymes.

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“…Indeed, aromatic oxidation in human liver microsomes occurred more readily with the (S)-enantiomer, while N-demethylation was the major route for the (R)-enantiomer. At low drug concentrations, cytotoxicity toward human mononuclear leukocytes was due to (R)-mianserin more than to (S)-mianserin, and showed a significant correlation with N-demethylation (RILEY et al 1989). Thus for mianserin toxicity was associated with N-demethylation rather than aromatic oxidation, while the reverse appeared true for disopyramide.…”

Section: Disopyramide (Fig 2a) Is a Chiral Antiarrhythmic Agent Markmentioning

confidence: 85%

Stereoselectivity in Metabolic Reactions of Toxication and Detoxication

Mayer¹,

Testa²

1994

Pharmacokinetics of Drugs

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The present chapter does not aim to review the whole field of stereos elective xenobiotic metabolism and disposition (which many general reviews have already covered), but rather to focus on its significance in molecular toxicology. By the latter term, we mean the study of metabolic reactions of toxication and detoxication which affect drugs and all other classes of xenobiotics.Drugs and other xenobiotics can elicit wanted effects (e.g., therapeutic response, parasite destruction) or unwanted effects (e.g., exaggerated pharmacological response, acute or chronic toxicity), both of which can be due to the parent compound and/or its metabolite(s). Considering only unwanted effects, i.e., toxicity, three situations can be schematized which emphasize the role of biotransformation in molecular toxicology and give an operational definition of toxication and detoxication.A first possibility (Fig. lA) is for the xenobiotic to be nontoxic but to give rise to a toxic metabolite (Ml)' Very often, this reaction of toxication is competitive with other biotransformation reaction(s) which lead to inactive metabolite(s) (M2) , and as a rule, the toxic metabolite Ml is itself transformed into an inactive metabolite (M3) in a typical reaction of detoxication.A second possibility (Fig. lB) is for the xenobiotic and its metabolite Ml to be toxic, in which case both metabolites M2 and M3 are products of detoxication reactions. A third possibility, by far the least frequent when chronic toxicity is concerned, is for only the xenobiotic to be toxic and all its metabolites to be inactive -a situation involving only reactions of detoxication.How does stereo selectivity enter this scene and what is its role? These questions will be answered in Sects. C and D using selected and representative examples, but not before some general principles of stereos elective xenobiotic metabolism are briefly presented. B. Principles of Stereoselective Xenobiotic Metabolism I. Chiral Recognition and Stereoselective Processes in Xenobiotic Metabolism and DispositionOne of the fundamental principles of pharmacodynamics, as formulated by Paul Ehrlich, is that compounds do not act unless bound. However, this rule is of such significance and scope that, far from being restricted to pharmacodynamic events, it also applies to pharmacokinetic and toxicokinetic events. Indeed, many processes in xenobiotic metabolism and disposition involve binding to biological macromolecules or macromolecular assemblies, covering a continuum of energies ranging from weak reversible bonds to covalent bonds. The only pharmacokinetic events not involving biological binding stricto sensu are reactions of non-enzymatic biotransformation (TESTA 1982) Stereoselectivity in Metabolic Reactions 211 and processes of passive diffusion (transport, excretion), although the passive partitioning into membranes is based on the same weak interactions as reversible binding and is thus conceptually comparable.These molecular processes are necessary for a proper understanding of the fact that the ena...

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A stereochemical investigation of the cytotoxicity of mianserin metabolites in vitro.

Cited by 14 publications

References 28 publications

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Liabilities Associated with the Formation of “Hard” Electrophiles in Reactive Metabolite Trapping Screens

Elucidation of the structural requirements for the bioactivation of mianserin in-vitro

Stereoselectivity in Metabolic Reactions of Toxication and Detoxication

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