Analysis of tamoxifen and its metabolites in synthetic gastric fluid digests and urine samples using high-performance liquid chromatography with electrospray mass spectrometry

Li, Xing‐Fang; Carter, Spencer; Dovic̀hi, Norman J.; Zhao, Jane Y.; Kovarik, Peter; Sakuma, Takeo

doi:10.1016/s0021-9673(01)00538-6

Cited by 20 publications

(20 citation statements)

References 24 publications

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“…Tamoxifen is mainly metabolized to N-oxide, N-desmethyl, a-hydroxy, and 4-hydroxy metabolites De Vos et al 2001;Li et al 2001;MacCallum et al 2000). Multiple CYPs including CYP 1A1, 2D6, 3A4, 2B6, and 3A5 are involved in the metabolism of tamoxifen to reactive catechol products that have the potential to form protein and DNA adducts (Davis et al 1998;Dehal and Kupfer 1999;Fan and Bolton 2001;Notley et al 2002).…”

Section: Tamoxifenmentioning

confidence: 99%

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Srivastava¹,

Maggs²,

Antoine³

et al. 2009

Handbook of Experimental Pharmacology

132

117

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Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites.

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Section: Tamoxifenmentioning

confidence: 99%

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity

Srivastava¹,

Maggs²,

Antoine³

et al. 2009

Handbook of Experimental Pharmacology

132

117

View full text Add to dashboard Cite

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“…[32,33] However, it has also been shown that (Z)-Htam and (E)-Htam will rapidly isomerize in vitro and in vivo, and the mixture of isomers has overall antagonist activity, since the (Z)-Htam binds to ER much more tightly than (E)-Htam. [33,34] Therefore, though NB-Htam may be photoisomerized upon irradiation, uncaged Htam shows full antagonist activity in culture.…”

Section: Introductionmentioning

confidence: 99%

Light‐Activated Transcription and Repression by Using Photocaged SERMs

Shi¹,

Koh²

2004

ChemBioChem

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Recently developed methods to regulate the spatial and temporal patterning of genes in a light-directed manner hold promise as powerful tools for exploring the function of genes that act through their unique spatiotemporal patterning. To further explore the application of photocaged ligands of nuclear receptors to control gene expression patterning, the actions of photocaged analogues of selective estrogen-receptor modulators (SERMs) have been evaluated. Photocaged derivatives of hydroxytamoxifen (NB-Htam) and guanidine tamoxifen (NB-Gtam) have been synthesized that selectively antagonize ER alpha- and ER beta-mediated transcription at classic estrogen response elements (EREs) in response to light. When present only intracellularly, Htam and Gtam provide a similar transient repression response. When SERMs are allowed to diffuse out of the cell, transcription is recovered at a similar rate for Htam and Gtam (6.4 and 5.6 h(-1)), but is notably faster than is observed with the covalently binding SERM tamoxifen aziridine (Taz) (3.8 h(-1)). This suggests that the duration of agonist action is controlled by ligand off-rates/diffusion and not by receptor turnover. Gtam activates ER beta-mediated transcription at AP1 sites in a similar way to what has previously been reported for Htam. NB-Gtam and NB-Tam provide a light-activated transcription response at AP1-driven reporters, thus illustrating the unique ability of photocaged SERMs to simultaneously mediate light-activated transcription and repression.

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“…Several papers describe the use of pure methanol as SL [16,[33][34][35][36]. Methanol as a protic solvent is well compatible with the ESI process.…”

Section: Sheath-liquid Compositionmentioning

confidence: 99%