PMID- 24657178
OWN - NLM
STAT- MEDLINE
DCOM- 20150105
LR  - 20151119
IS  - 1873-6351 (Electronic)
IS  - 0278-6915 (Linking)
VI  - 68
DP  - 2014 Jun
TI  - Systemic toxicity induced by paclitaxel in vivo is associated with the solvent 
      cremophor EL through oxidative stress-driven mechanisms.
PG  - 78-86
LID - S0278-6915(14)00142-2 [pii]
LID - 10.1016/j.fct.2014.03.013 [doi]
AB  - The toxic effects of paclitaxel (PTX) and its solubilizing agent cremophor EL 
      (CREL) have been well established in vitro; however, the in vivo mechanisms 
      underlying this toxicity remain unclear. Thus, the aim of this study was to 
      analyze the in vivo toxicity induced by infusion of PTX and CREL and to 
      investigate the involvement of oxidative stress as a potential mechanism for this 
      toxicity. We treated male Wistar rats with PTX and/or CREL for 1h using 
      human-equivalent doses (PTX+CREL/ethanol+NaCl 175mg/m(2) or CREL+ethanol+NaCl) 
      and sacrificed immediately or 24h after these drug infusions to systemic 
      biochemical evaluations. Hidrosoluble vitamin E (vitE, Trolox) was added as a 
      control in some groups. The oxidative profile was determined by measuring 
      erythrocyte and plasma lipid peroxidation, superoxide dismutase and catalase 
      activities, reduced glutathione (GSH) levels, red blood cell (RBC) counts, 
      hemoglobin profile, plasma total radical-trapping antioxidant parameter (TRAP), 
      plasma lipid peroxidation, nitric oxide levels and malondialdehyde levels. Our 
      findings showed that CREL infusion triggered immediate high plasma lipid 
      peroxidation and augmented TRAP, while PTX caused immediate TRAP consumption and 
      metahemoglobin formation. Pronounced oxidative effects were detected 24h after 
      infusion, when CREL treatment enhanced RBC counts and plasma lipid peroxidation, 
      increased catalase activity, and decreased TRAP levels. On the other hand, after 
      24h, PTX-infused rats showed reduced catalase activity and reduced metahemoglobin 
      levels. These data indicate the existence of a continuous oxidative stress 
      generation during CREL-PTX treatment and highlight CREL as primarily responsible 
      for the in vivo oxidative damage to RBCs.
CI  - Copyright (c) 2014 Elsevier Ltd. All rights reserved.
FAU - Campos, Fernanda C
AU  - Campos FC
AD  - Laboratory of Physiopathology and Free Radicals, Department of Pathology, State 
      University of Londrina, Londrina, Parana, Brazil.
FAU - Victorino, Vanessa J
AU  - Victorino VJ
AD  - Faculty of Medicine, Universidade de Sao Paulo, Sao Paulo, Brazil.
FAU - Martins-Pinge, Marli Cardoso
AU  - Martins-Pinge MC
AD  - Department of Physiological Sciences, State University of Londrina, Londrina, 
      Parana, Brazil.
FAU - Cecchini, Alessandra L
AU  - Cecchini AL
AD  - Laboratory of Physiopathology and Free Radicals, Department of Pathology, State 
      University of Londrina, Londrina, Parana, Brazil.
FAU - Panis, Carolina
AU  - Panis C
AD  - Laboratory of Physiopathology and Free Radicals, Department of Pathology, State 
      University of Londrina, Londrina, Parana, Brazil; State University of West 
      Parana, UNIOESTE, Francisco Beltrao, Parana, Brazil.. Electronic address: 
      carolpanis@sercomtel.com.br.
FAU - Cecchini, Rubens
AU  - Cecchini R
AD  - Laboratory of Physiopathology and Free Radicals, Department of Pathology, State 
      University of Londrina, Londrina, Parana, Brazil.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140319
PL  - England
TA  - Food Chem Toxicol
JT  - Food and chemical toxicology : an international journal published for the British 
      Industrial Biological Research Association
JID - 8207483
RN  - 0 (Antineoplastic Agents, Phytogenic)
RN  - 0 (Hemoglobins)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 4Y8F71G49Q (Malondialdehyde)
RN  - 6D4M1DAL6O (cremophor EL)
RN  - EC 1.11.1.6 (Catalase)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - GAN16C9B8O (Glutathione)
RN  - P88XT4IS4D (Paclitaxel)
RN  - PDC6A3C0OX (Glycerol)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents, Phytogenic/*toxicity
MH  - Catalase/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Evaluation, Preclinical
MH  - Erythrocyte Count
MH  - Erythrocytes/drug effects/metabolism
MH  - Glutathione/blood
MH  - Glycerol/*analogs & derivatives/toxicity
MH  - Hemoglobins/metabolism
MH  - Lipid Peroxidation/drug effects
MH  - Male
MH  - Malondialdehyde/blood
MH  - Nitric Oxide/blood
MH  - Oxidative Stress/*drug effects
MH  - Paclitaxel/*toxicity
MH  - Rats
MH  - Rats, Wistar
MH  - Superoxide Dismutase/blood
OTO - NOTNLM
OT  - Cremophor
OT  - Hematological toxicity
OT  - Oxidative stress
OT  - Paclitaxel
EDAT- 2014/03/25 06:00
MHDA- 2015/01/06 06:00
CRDT- 2014/03/25 06:00
PHST- 2013/10/10 00:00 [received]
PHST- 2014/03/05 00:00 [revised]
PHST- 2014/03/07 00:00 [accepted]
PHST- 2014/03/25 06:00 [entrez]
PHST- 2014/03/25 06:00 [pubmed]
PHST- 2015/01/06 06:00 [medline]
AID - S0278-6915(14)00142-2 [pii]
AID - 10.1016/j.fct.2014.03.013 [doi]
PST - ppublish
SO  - Food Chem Toxicol. 2014 Jun;68:78-86. doi: 10.1016/j.fct.2014.03.013. Epub 2014 
      Mar 19.