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Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds
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Chemiluminescence-based Assays for Detection of Nitric Oxide and its Derivatives from Autoxidation and Nitrosated Compounds

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Nitrosation, nitration, and autoxidation of the selective estrogen receptor modulator raloxifene by nitric oxide,

Violeta Toader1, Xudong Xu, Adrian Nicolescu

  • 1Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 Wood Street, Chicago, Illinois 60612-7231, USA.

Chemical Research in Toxicology
|October 21, 2003
PubMed

Insights

Selective estrogen receptor modulators (SERMs) can form toxic reactive nitrogen/oxygen species (RNOS). Raloxifene and estradiol react with RNOS, forming nitration and oxidation products, indicating potential SERM toxicity pathways.

Area of Science:

  • Chemical toxicology
  • Pharmacology
  • Biochemistry

Background:

  • Selective estrogen receptor modulators (SERMs) are used for cancer chemoprevention and osteoporosis.
  • Evidence suggests SERMs may have carcinogenic properties.
  • SERMs, like raloxifene, elevate nitric oxide (NO) levels in tissues.

Purpose of the Study:

  • To investigate the reactions of estradiol (E(2)), raloxifene, and its isomer with NO and reactive nitrogen/oxygen species (RNOS).
  • To identify potential toxicity pathways associated with SERM use.

Main Methods:

  • Examined reactions of E(2) and raloxifene with peroxynitrite and RNOS generated from NO(2)(-)/H(2)O(2) systems.
  • Characterized nitration, oxidation, and nitrosation products.
  • Investigated reactions with glutathione (GSH) and NO in aerobic solution.

Main Results:

  • Peroxynitrite caused aromatic ring nitration of E(2) and benzothiophenes.
  • Raloxifene and its isomer formed oxidation and nitrosation products, including a dimer and quinone oxime derivative.
  • Raloxifene readily autoxidized in the presence of NO, forming oxidation products similar to those from RNOS.

Conclusions:

  • SERMs can react with NO and RNOS to form potentially toxic compounds.
  • The formation of quinone oximes and autoxidation of raloxifene represent novel findings in SERM metabolism.
  • These reactions highlight significant pathways for SERM chemical toxicology.

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