Metabolic activation and drug toxicity

Nelson, Sidney D.

doi:10.1021/jm00349a001

Cited by 191 publications

(88 citation statements)

References 13 publications

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“…By our hypothesis, alkylation of proteins by atropaldehyde may result in the generation of antigens that precipitate an immune response, in a manner similar to mechanisms of immune-mediated toxicity for other agents (14)(15)(16)(17)(18)(19). If the toxicity due to atropaldehyde is immune mediated, then susceptibility to this toxicity will be a function not only of the formation of atropaldehydeprotein conjugates but also of a patient's immune-system phenotype.…”

Section: Discussionmentioning

confidence: 89%

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

et al. 1999

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Summary:Purpose: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropionaldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine.Methods: We summarize the results of an LClMS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population.Results: Analysis was performed on 3 I patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured.Conclusions: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.

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Section: Discussionmentioning

confidence: 89%

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

et al. 1999

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“…They are frequently used as substrates and authentic standards in studies of drug bioavailability, pharmacodynamics and pharmacokinetics [1][2][3]. In vivo, the C-H bonds of pharmaceuticals are predominantly oxygenated by liver cytochrome P450-monooxygenases (P450s) to yield more polar HDMs that are excreted directly or as conjugates [4].…”

Section: Introductionmentioning

confidence: 99%

Preparation of human drug metabolites using fungal peroxygenases

Poraj-Kobielska

Kinne

Ullrich

et al. 2011

Biochemical Pharmacology

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The synthesis of hydroxylated and O-or N-dealkylated human drug metabolites (HDMs) via selective monooxygenation remains a challenging task for synthetic organic chemists. Here we report that aromatic peroxygenases (APOs; EC 1.11.2.1) secreted by the agaric fungi 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64

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“…Although P450-mediated metabolism usually leads to detoxification, bioactivation and reactive metabolites formation can occur, increasing the risk of drug-induced liver injuries (Mitchell et al, 1973;Dahlin et al, 1984;Leung et al, 2012). A key differentiating factor for a xenobiotic to form a benign, oxidative metabolite or a reactive metabolite is the innate chemistry of the xenobiotic (Nelson, 1982). The term structural alert classifies a set of chemical functional groups prone to P450-mediated reactive metabolite formation (Kalgutkar and Didiuk, 2009;Stepan et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 Architecture and Cysteine Nucleophile Placement Impact Raloxifene-Mediated Mechanism-Based Inactivation

VandenBrink¹,

Davis²,

Pearson³

et al. 2012

Mol Pharmacol

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The propensity for cytochrome P450 (P450) enzymes to bioactivate xenobiotics is governed by the inherent chemistry of the xenobiotic itself and the active site architecture of the P450 enzyme(s). Accessible nucleophiles in the active site or egress channels of the P450 enzyme have the potential of sequestering reactive metabolites through covalent modification, thereby limiting their exposure to other proteins. Raloxifene, a drug known to undergo CYP3A-mediated reactive metabolite formation and time-dependent inhibition in vitro, was used to explore the potential for bioactivation and enzyme inactivation of additional P450 enzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A5). Every P450 tested except CYP2E1 was capable of raloxifene bioactivation, based on glutathione adduct formation. However, raloxifene-mediated timedependent inhibition only occurred in CYP2C8 and CYP3A4. for CYP2C8 and CYP3A4, respectively. Proteolytic digests of CYP2C8 and CYP3A4 Supersomes revealed adducts to Cys225 and Cys239 for CYP2C8 and CYP3A4, respectively. For each P450 enzyme, proposed substrate/metabolite access channels were mapped and active site cysteines were identified, which revealed that only CYP2C8 and CYP3A4 possess accessible cysteine residues near the active site cavities, a result consistent with the observed kinetics. The combined data suggest that the extent of bioactivation across P450 enzymes does not correlate with P450 inactivation. In addition, multiple factors contribute to the ability of reactive metabolites to form apo-adducts with P450 enzymes.

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Metabolic activation and drug toxicity

Cited by 191 publications

References 13 publications

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

Preparation of human drug metabolites using fungal peroxygenases

Cytochrome P450 Architecture and Cysteine Nucleophile Placement Impact Raloxifene-Mediated Mechanism-Based Inactivation

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