Correlation between induction of DNA fragmentation in lung cells from rats and humans and carcinogenic activity.
Six chemicals, known to induce lung tumors in rats, were examined for their ability to induce DNA fragmentation in primary cultures of rat and human lung cells, and in the lung of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the single-cell gel electrophoresis (Comet) assay, were obtained in primary lung cells from male rats with the following, minimally toxic, concentrations of the six test compounds: N-nitrosodimethylamine (NDMA; 2.5-10 mM), hydrazine (HZ; 0.5-4 mM), cadmium sulfate (CD; 31.2 and 62.5 μM), 4,4'-methylene bis (2-chloroaniline) (MOCA; 31.2-125 μM), isobutyl nitrite (IBN; 7.8-31.2 μM) and tetranitromethane (TNM; 1.9-15.6 μM). Similar degrees of DNA fragmentation were obtained in primary human lung cells; however, due to inter-donor differences, the minimum effective concentrations were in some donors lower and in others higher than in rats, and IBN induced DNA damage only in one of three donors. The DNA-damaging potency of HZ was higher in rats than in humans, and the opposite was true for MOCA. In agreement with these findings, statistically significant increases in the average frequency of DNA breaks were obtained in the lung of rats given a single oral dose (1/2 LD50) of the six test compounds. These findings give evidence that genotoxic lung carcinogens may be identified by use of the DNA fragmentation/Comet assay on rat lung cells as targets cells, and show that the six compounds tested produce in primary cultures of lung cells from human donors DNA-damaging effects substantially similar to those observed in rats.
Robbiano
Luigi
L
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, Viale Benedetto XV, 2, I-16132 Genoa, Italy.
Baroni
Debora
D
Novello
Luca
L
Brambilla
Giovanni
G
D000230:Adenocarcinoma / Q000473:pathology*; D000368:Aged; D000818:Animals; D019187:Cadmium Compounds / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D020552:Comet Assay; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects*; D053938:DNA Fragmentation / Q000187:drug effects*; D004128:Dimethylnitrosamine / Q000633:toxicity; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000633:toxicity; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008753:Methylenebis(chloroaniline) / Q000633:toxicity; D008875:Middle Aged; D009573:Nitrites / Q000633:toxicity; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D013431:Sulfates / Q000633:toxicity; D013774:Tetranitromethane / Q000633:toxicity; D059016:Tumor Microenvironment
D019187:Cadmium Compounds; D002273:Carcinogens; D006834:Hydrazines; D009573:Nitrites; D013431:Sulfates; C029424:hydrazine; D008753:Methylenebis(chloroaniline); C037123:cadmium sulfate; C018086:isobutyl nitrite; D013774:Tetranitromethane; D004128:Dimethylnitrosamine