Mechanism of the salutary effects of flutamide on intestinal myeloperoxidase activity following trauma-hemorrhage: up-regulation of estrogen receptor-{beta}-dependent HO-1.

Abstract

Hemeoxygenase (HO)-1 induction following adverse circulatory conditions is known to be protective, and precastrated males have less intestinal damage than sham-operated males following trauma-hemorrhage (T-H). Previous studies have also shown that administration of flutamide up-regulated estrogen receptor (ER) expression in males following T-H. We hypothesized that flutamide administration in males following T-H up-regulates HO-1 via an ER-dependent pathway and protects against intestinal injury. Male Sprague-Dawley rats underwent T-H [mean blood pressure (MBP) 40 mmHg for 90 min and then resuscitation]. A single dose of flutamide (25 mg/kg body weight), with or without an ER antagonist (ICI 182,780), a HO enzyme inhibitor [chromium-mesoporphyrin (CrMP)], or vehicle, was administered subcutaneously during resuscitation. At 2 h after T-H or sham operation, intestinal myeloperoxidase (MPO) activity, intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, and CINC-3 levels were measured. Intestinal ER-alpha, ER-beta, androgen receptor, and HO-1 mRNA/protein levels were also determined. Results showed that T-H increased intestinal MPO activity, ICAM-1, CINC-1, and CINC-3 levels. These parameters were improved significantly in the flutamide-treated rats subjected to T-H. Flutamide treatment increased intestinal HO-1 and ER-beta mRNA/protein levels as compared with vehicle-treated T-H rats. Administration of the ER antagonist ICI 182,780 or the HO inhibitor CrMP prevented the flutamide-induced attenuation of shock-induced intestinal damage. Thus, the salutary effects of flutamide administration on attenuation of intestinal injury following T-H are mediated via up-regulation of ER-beta-dependent HO-1 expression.

• Authors: Huang-Ping Yu, Mashkoor A Choudhry, Tomoharu Shimizu, Ya-Ching Hsieh, Martin G Schwacha, Shaolong Yang, Irshad H Chaudry
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 79 Issue 2 Pg. 277-84 (Feb 2006) ISSN: 0741-5400 [Print] United States
• PMID: 16330533 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Chemokine CXCL1
• Chemokines, CXC
• Cxcl1 protein, rat
• Enzyme Inhibitors
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Mesoporphyrins
• RNA, Messenger
• chromium mesoporphyrin
• Intercellular Adhesion Molecule-1
• Fulvestrant
• Estradiol
• Flutamide
• Peroxidase
• Heme Oxygenase-1

Topics

• Animals
• Chemokine CXCL1
• Chemokines, CXC (metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor alpha (antagonists & inhibitors, metabolism)
• Estrogen Receptor beta (antagonists & inhibitors, genetics, metabolism)
• Flutamide (administration & dosage, antagonists & inhibitors)
• Fulvestrant
• Gene Expression Regulation, Enzymologic (drug effects)
• Heme Oxygenase-1 (antagonists & inhibitors, genetics, metabolism)
• Hemorrhage (physiopathology)
• Intercellular Adhesion Molecule-1 (metabolism)
• Intestines (drug effects, enzymology, injuries)
• Male
• Mesoporphyrins (pharmacology)
• Peroxidase (drug effects, metabolism)
• RNA, Messenger (drug effects, genetics)
• Rats
• Rats, Sprague-Dawley
• Up-Regulation (drug effects)