Aziridine biotransformation by microsomes and lethality to hepatocytes isolated from rat.
To clarify the relationship of aziridine biotransformation to their cytotoxic activities, the metabolism of optical isomers of typical cytotoxic and non-cytotoxic aziridines was studied in isolated hepatocytes, rat liver microsomes, mitochondria and L-1210 mouse leukemia cells. Cytotoxic 1-methyl-2-beta-naphthylaziridine (NAZ) gave nitrosomethane as one of the bioactivation products in isolated hepatocytes and simultaneously induced a marked decrease in cellular ATP followed by cell lethality. NAZ itself did not directly affect the respiratory function of mitochondria in isolated hepatocytes or in buffer solution, however, it inhibited the mitochondrial activity in the presence of microsomes in the buffer solution. Nitroso-t-butane or nitrosomethane dimer, used as a substitute for extremely labile nitrosomethane, strongly inhibited the respiration of mitochondria. On the other hand, optical isomers of 2-aziridinecarboxylic acid (AZC) which did not give nitrosomethane in isolated hepatocytes or microsomes also did not show cytotoxicity. Thus, the cytotoxicity of NAZ seems to be induced by bioactivation via cellular oxidases with the nitrosomethane generated being a major toxic component. This may occur with most of the cytotoxic aziridine derivatives.
Hata
Y
Y
Shionogi Research Laboratories, Shionogi & Co., Ltd., Osaka, Japan.
Watanabe
M
M
Tonda
K
K
Hirata
M
M
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001388:Aziridines / Q000378:metabolism / Q000633:toxicity*; D001389:Azirines / Q000633:toxicity*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D007536:Isomerism; D007939:Leukemia L1210 / Q000378:metabolism; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D001388:Aziridines; D001389:Azirines; C016939:250059-S; C033132:aziridine; D000255:Adenosine Triphosphate