Correlation between induction of DNA fragmentation and micronuclei formation in kidney cells from rats and humans and tissue-specific carcinogenic activity.
Five chemicals, known to induce kidney tumors in rats, were assayed for their ability to induce DNA damage and formation of micronuclei in primary cultures of rat and human kidney cells and in the kidney of intact rats. Significant dose-dependent increases of DNA fragmentation, as measured by the Comet assay, and of micronuclei frequency were obtained in primary kidney cells from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and potassium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1, 4-dichlorobenzene and nitrilotriacetic acid from 1.8 to 5.6 mM. In terms of DNA-damaging potency all the five chemicals were more active in rat than in human kidney cells, whereas the potencies in inducing micronuclei formation were similar in the two species with the exception of 1,4-dichlorobenzene, which was slightly more potent in human than in rat cells. Consistently with the results observed in vitro, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were detected in the kidney of rats given po a single (12 LD50) or three successive daily doses (13 LD50) of the five test compounds. 4, 4'-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative responses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays using as target kidney cells and show that the five chemicals tested produce in primary cultures of kidney cells from human donors effects similar to those observed in rats.
Robbiano
L
L
Division of Clinical Pharmacology, University of Genoa, Genoa, I-16132, Italy.
Carrozzino
R
R
Puglia
C P
CP
Corbu
C
C
Brambilla
G
G
D000328:Adult; D000814:Aniline Compounds / Q000633:toxicity; D000818:Animals; D001959:Bromates / Q000633:toxicity; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D002722:Chlorobenzenes / Q000633:toxicity; D020552:Comet Assay; D053938:DNA Fragmentation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D008297:Male; D015162:Micronucleus Tests; D008875:Middle Aged; D009571:Nitrilotriacetic Acid / Q000633:toxicity; D009942:Organometallic Compounds / Q000633:toxicity; D010615:Phenacetin / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D001559:Benzhydryl Compounds
D000814:Aniline Compounds; D001959:Bromates; D002273:Carcinogens; D002722:Chlorobenzenes; D009571:Nitrilotriacetic Acid; D009942:Organometallic Compounds; D010615:Phenacetin; C019536:potassium bromate; C018511:4-dichlorobenzene; C009505:4,4'-diaminodiphenylmethane; D001559:Benzhydryl Compounds; C008261:lead acetate