Factors influencing the induction of DNA single strand breaks in rats by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).
The ability of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to induce lipid peroxidation and DNA damage in rat hepatic nuclei was investigated. In addition, the role of iron in hepatic DNA damage was examined. Female Sprague-Dawley rats were treated with a single dose of 25--100 micrograms TCDD/kg orally, and sacrificed 3-14 days after treatment. Liver nuclei were isolated, and DNA single strand breaks (DNA-SSB) and lipid peroxidation were determined. Lipid peroxidation was assessed by measuring the content and production of thiobarbituric acid reactive substances (TBARS) while DNA-SSB were determined by the alkaline elution technique. The results demonstrate that TCDD dose and time-dependent increases in hepatic nuclear TBARS content and production occur in conjunction with an increase in DNA-SSB. The administration of the dithiolthione antioxidant oltipraz (30 mg/kg/day for 10 days) resulted in a significant decrease (47%) in the incidence of TCDD-induced DNA-SSB. Clofibrate administration (100 mg/kg/day for 12 days) and pair feeding had no effect on TCDD-induced DNA-SSB. The incubation of hepatic microsomes and mitochondria from TCDD-treated rats with nuclei from untreated animals for one hr at 37 degrees C resulted in enhanced DNA damage which was abolished by the addition of 0.10 mM desferrioxamine (DFX). Incubation with cytosol had no significant effect. Incubation of 0.10 mM Fe2+ or Fe3+ with isolated hepatic nuclei from untreated rats produced significant increases in DNA-SSB, which were abolished by the addition of 0.10 mM DFX to the incubation medium. TCDD may produce an increased bioavailability of iron which leads to enhanced DNA single strand breaks and lipid peroxidation in hepatic nuclei.
Wahba
Z Z
ZZ
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68105-1065.
Lawson
T W
TW
Murray
W J
WJ
Stohs
S J
SJ
D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects; D004249:DNA Damage; D004277:DNA, Single-Stranded / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007501:Iron / Q000494:pharmacology; D008054:Lipid Peroxides / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008315:Malondialdehyde / Q000032:analysis; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013347:Subcellular Fractions / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors
D004277:DNA, Single-Stranded; D008054:Lipid Peroxides; D011719:Pyrazines; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D013871:Thiones; D013876:Thiophenes; D008315:Malondialdehyde; C026209:oltipraz; D007501:Iron