Tissue distribution of DNA adducts in male Fischer rats exposed to 500 ppm of propylene oxide: quantitative analysis of 7-(2-hydroxypropyl)guanine by 32P-postlabelling.
7-(2-Hydroxypropyl)guanine (7-HPG) constitutes the major adduct from alkylation of DNA by the genotoxic carcinogen, propylene oxide. The levels of 7-HPG in DNA of various organs provides a relevant measure of tissue dose. 7-Alkylguanines can induce mutation through abasic sites formed from spontaneous depurination of the adduct. In the current study the formation of 7-HPG was investigated in male Fisher 344 rats exposed to 500 ppm of propylene oxide by inhalation for 6 h/day, 5 days/week, for up to 20 days. 7-HPG was analyzed using the 32P-postlabelling assay with anion-exchange cartridges for adduct enrichment. In animals sacrificed directly following 20 days of exposure, the adduct level was highest in the respiratory nasal epithelium (98.1 adducts per 10(6) nucleotides), followed by olfactory nasal epithelium (58.5), lung (16.3), lymphocytes (9.92), spleen (9.26), liver (4.64), and testis (2.95). The nasal cavity is the major target for tumor induction in the rat following inhalation. This finding is consistent with the major difference in adduct levels observed in nasal epithelium compared to other tissues. In rats sacrificed 3 days after cessation of exposure, the levels of 7-HPG in the aforementioned tissues had, on the average, decreased by about one-quarter of their initial concentrations. This degree of loss closely corresponds to the spontaneous rate of depurination for this adduct (t 1/2 = 120 h), and suggests a low efficiency of repair for 7-HPG in the rat. The postlabelling assay used had a detection limit of one to two adducts per 10(8) nucleotides, i.e. it is likely that this adduct could be analyzed in nasal tissues of rats exposed to less than 1 ppm of propylene oxide.
Segerbäck
D
D
Center for Nutrition and Toxicology, Department of Biosciences, Karolinska Institute, Novum, Huddinge, Sweden. dan.segerback@cnt.ki.se
Plná
K
K
Faller
T
T
Kreuzer
P E
PE
Hakansson
K
K
Filser
J G
JG
Nilsson
R
R
D000280:Administration, Inhalation; D000478:Alkylation; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts / Q000032:analysis*; D004852:Epoxy Compounds / Q000633:toxicity*; D006147:Guanine / Q000032:analysis* / Q000378:metabolism / Q000031:analogs & derivatives; D007553:Isotope Labeling; D008297:Male; D010761:Phosphorus Radioisotopes; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
C116199:7-(2-hydroxypropyl)guanine; D002273:Carcinogens; D018736:DNA Adducts; D004852:Epoxy Compounds; D010761:Phosphorus Radioisotopes; D006147:Guanine; C009068:propylene oxide