Reduction of bleomycin-induced acute DNA injury in the rat lung by the 21-aminosteroid, U-74389G.
OBJECTIVE
To determine whether pretreatment with a 21-aminosteroid, U-74389G, can prevent subsequent DNA injury in bleomycin-exposed lungs.


METHODS
Thirty-six adult male Sprague-Dawley rats.


METHODS
Controlled animal laboratory investigation of DNA injury in vivo.


METHODS
Animals were treated with 21-aminosteroid (10 mg/kg) or vehicle and subsequently received intratracheal instillation of bleomycin (1.75 U) or normal saline.


RESULTS
Twenty-four hours after bleomycin exposure, the 21-aminosteroid-treated animals had decreased evidence of DNA injury, expressed as percentage of DNA fragmentation normalized to the control group (113.5 +/- 6 [SEM] vs. 132 +/- 3.9%, p < or = .05), and activity of the DNA repair enzyme poly ADP-ribose synthetase (3.4 +/- 0.2 vs. 5.6 +/- 0.9 pmol nicotinamide adenine dinucleotide/min/mg protein, p < or = .05). Only bleomycin-exposed (+ vehicle) animals demonstrated significant evidence of increased DNA injury vs. the intratracheal saline-exposed control groups.


CONCLUSIONS
The 21-aminosteroid pretreatment decreases subsequent pulmonary DNA injury induced by bleomycin exposure. This finding is likely due to the 21-aminosteroid's iron-chelating and cell-permeating abilities, and suggests that these agents may be effective in other diseases where iron-dependent free radical reactions occur.
Dallessio
J J
JJ
Division of Pediatric Critical Care, University of Miami School of Medicine, FL 33101, USA.
McLaughlin
G E
GE
Frank
L
L
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects* / Q000378:metabolism; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D001761:Bleomycin / Q000009:adverse effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects; D007502:Iron Chelating Agents / Q000378:metabolism; D008025:Ligases / Q000032:analysis; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011281:Pregnatrienes / Q000378:metabolism / Q000627:therapeutic use*; D011292:Premedication; D051381:Rats; D017207:Rats, Sprague-Dawley
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D007502:Iron Chelating Agents; D011281:Pregnatrienes; D001761:Bleomycin; C074965:U 74389F; D011064:Poly Adenosine Diphosphate Ribose; D008025:Ligases