Comparative study of DNA damage and repair induced by ten N-nitroso compounds in primary cultures of human and rat hepatocytes.
Ten carcinogenic N-nitroso compounds were assayed for DNA-damaging activity in primary cultures of human and rat hepatocytes. DNA fragmentation was measured by the alkaline elution technique, and unscheduled DNA synthesis by quantitative autoradiography. Positive dose-related responses in the range of subtoxic concentrations indicated were obtained in cells of both species with N-nitrosodiethylamine (10-32 mM), N-nitrosodi-n-propylamine (1.8-10 mM), N-nitrosomorpholine (1-3.2 mM), N-nitrosopiperidine (1-3.2 mM), N-nitrosopyrrolidine (3.2-18 mM), N-nitroso-N-methylurea (0.32-1.8 mM), N-nitroso-N-ethylurea (0.32-1.8 mM), and N-nitroso-N-butylurea (0.1-0.32 mM). N-nitrosodi-n-butylamine was practically inactive at the maximal soluble concentration (1 mM). The responses of human hepatocytes were qualitatively similar to those of rat hepatocytes, but statistically significant differences between the two species in the amounts of DNA damage and/or unscheduled DNA synthesis were observed with N-nitrosodimethylamine, N-nitrosomorpholine, N-nitrosopiperidine, N-nitrosopyrrolidine, and N-nitroso-N-butylurea. On the other hand, quantitative differences in the genotoxic effects induced by 5 mM N-nitrosodimethylamine in cultures derived from 20 human donors and from 20 rats were greater than average interspecies differences displayed by this nitrosamine and by other N-nitroso compounds. These results indicate that the rat hepatocyte DNA repair assay is a valid model for predicting the genotoxic potential of N-nitroso compounds in human hepatocytes.
Martelli
A
A
Institute of Pharmacology, University of Genoa, Italy.
Robbiano
L
L
Gazzaniga
G M
GM
Brambilla
G
G
D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008770:Methylnitrosourea / Q000494:pharmacology; D008875:Middle Aged; D009242:N-Nitrosopyrrolidine / Q000494:pharmacology; D009602:Nitrosamines / Q000494:pharmacology; D009603:Nitroso Compounds / Q000494:pharmacology*; D009607:Nitrosourea Compounds / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D009602:Nitrosamines; D009603:Nitroso Compounds; D009607:Nitrosourea Compounds; C013161:N-nitroso(di-n-propyl)amine; C002741:N-nitrosomorpholine; D008770:Methylnitrosourea; C002743:N-nitrosopiperidine; C002738:N-nitrosobutylurea; C012279:dibutylnitrosamine; D005038:Ethylnitrosourea; D009242:N-Nitrosopyrrolidine