Genotoxic activity of 1,3-dichloropropene in a battery of in vivo short-term tests.
The genotoxic activity of 1,3-dichloropropene, which has been classified as possibly carcinogenic to humans, was investigated in rats given high single doses of this chloroolefin. A dose-related amount of DNA fragmentation was observed at doses ranging from 62.5 to 250 mg/kg in liver and gastric mucosa, both of which are targets of DCP carcinogenic activity, as well as in the kidney. The frequency of DNA breaks, that were to a large extent repaired within 24 hr, was higher after po than after ip administration in the liver, while the converse occurred in the kidney. Any evidence of DNA fragmentation was, in contrast, absent in lung, bone marrow, and brain which are not sites of DCP-induced tumor development. A role of cytochrome P450 in the activation of DCP is suggested by the lower degree of liver DNA fragmentation observed in rats pretreated with methoxsalen. DCP produced a dose-dependent reduction of the liver GSH level, an effect that presumably hinders its detoxification and thus favors its DNA-damaging activity. In contrast with the satisfactory prediction of DCP carcinogenic activity provided by the results of the in vivo DNA damage/alkaline elution assay, neither the in vivo rat hepatocyte DNA repair assay nor the micronucleus assay, carried out on bone marrow, spleen, and liver cells of partially hepatectomized rats, supplied any evidence of DCP genotoxicity.
Institute of Pharmacology, University of Genoa, Italy.
M
M
Ghia
L
L
Robbiano
A
A
Allavena
A
A
Martelli
G
G
Brambilla
D000498:Allyl Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004249:DNA Damage; D004912:Erythrocytes / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects; D005978:Glutathione / Q000037:antagonists & inhibitors; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D008099:Liver / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D015162:Micronucleus Tests; D051381:Rats; D017207:Rats, Sprague-Dawley
D000498:Allyl Compounds; D065607:Cytochrome P-450 Enzyme Inhibitors; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; C023891:1,3-dichloro-1-propene; D005978:Glutathione