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 the ir ability to induce DNA damage and formation of micronuclei in primary cul tures of rat and human kidney cells and in the kidney of intact rats. Signi ficant dose-dependent increases of DNA fragmentation, as measured by the Co met assay, and of micronuclei frequency were obtained in primary kidney cel ls from both rats and humans with the following concentrations of the five test compounds: lead acetate (not tested for micronuclei induction) and pot assium bromate from 0.56 to 1.8 mM, phenacetin from 1 to 3.2 mM, and 1,4-di chlorobenzene 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 hu man kidney cells, whereas the potencies in inducing micronuclei formation w ere similar in the two species with the exception of 1,4-dichlorobenzene, w hich 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 (1/2 LD50) or three successive dai ly doses (1/3 LD50) of the five test compounds. 4,4'-Methylenedianiline, a carcinogen which does not induce kidney tumors in rats, gave negative respo nses in both in vitro and in vivo assays. These findings give evidence that kidney carcinogens may be identified by short-term genotoxicity assays usi ng as target kidney cells and show that the five chemicals tested produce i n primary cultures of kidney cells from human donors effects similar to tho se observed in rats. (C) 1999 Academic Press.