Comparative genotoxicities of procarbazine and two deuterated analogs in mammalian cells in vitro and in vivo.
N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine; 50-1000 micrograms/ml) induced DNA damage in hepatocytes measured by an automated alkaline elution method, whereas no significant increase in unscheduled DNA synthesis was seen. In hepatocytes isolated from PCB-treated rats, DNA damage was detected in both test systems at concentrations as low as 1-10 micrograms/ml. DNA damage, as measured by alkaline elution and sister-chromatid exchange(s), was observed also in V79 cells incubated with PCB-hepatocytes. In contrast, no mutagenic activity was observed in the Salmonella typhimurium strain TA1530 co-incubated with the hepatocytes. Exposure of rats to low doses of procarbazine (25-50 mg/kg) caused DNA damage measured by alkaline elution in liver and testis, with the liver being somewhat more sensitive. The genotoxicity caused by procarbazine was increased by a factor of 2-3 in both organs by PCB-treatment of the rats. N-isopropyl-alpha-(2-methyl-hydrazino)-p-[alpha,alpha-2H2]toluamide (d2-procarbazine), was found to cause significantly less genotoxicity in control rats than either procarbazine itself, or N-isopropyl-alpha-(2-[alpha,alpha,alpha-2H3]methylhydrazino)-p-tol uamide (d3-procarbazine). This indicates that benzylic C-H oxidation of procarbazine is an important step in the activation of procarbazine to genotoxic metabolites in uninduced rats.
Holme
J A
JA
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Brunborg
G
G
Hongslo
J K
JK
Trygg
B
B
Nelson
S D
SD
D000818:Animals; D001711:Biotransformation; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003903:Deuterium; D004305:Dose-Response Relationship, Drug; D008099:Liver; D008297:Male; D009152:Mutagenicity Tests; D011344:Procarbazine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000187:drug effects; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013737:Testis
D011344:Procarbazine; D004247:DNA; D003903:Deuterium