Toxicity of methylating agents in isolated hepatocytes.
To investigate the pathogenesis of hepatotoxicity by methylating agents, we exposed isolated hepatocytes to N-nitrosodimethylamine (NDMA), N-methyl-N'-nitro-N nitrosoguanidine (MNNG), N-methyl-N-nitrosourea (MNU), or methyl methanesulfonate (MMS). Although NDMA is a potent in vivo hepatotoxicant in rats, no evidence of hepatocyte injury, measured by the leakage of lactate dehydrogenase (LDH) activity into the medium, was observed following exposure to a 1-100 mM concentration of either NDMA or MNU. In contrast, exposure of hepatocytes to MMS or MNNG resulted in greater than or equal to 90% LDH release. These differences in toxicity were not related to the extent of covalent binding to hepatocytes. Following MMS or MNNG, but not MNU or NDMA exposure, a significant rise in the generation of thiobarbiturate (TBA)-reactive species was observed. When hepatocytes were exposed to the antioxidant promethazine prior to the addition of MMS or MNNG, the formation of TBA-reactive species was inhibited completely. Although promethazine blocked MNNG-mediated cell injury, the antioxidant had no effect on MMS intoxication. These data suggest that methylating agents can cause hepatotoxicity by more than a single mechanism. For MNNG, lipid peroxidation may be involved in the pathogenesis of acute hepatotoxicity.
Reitman
F A
FA
Department of Environmental Health, University of Cincinnati Medical Center, OH 45267-0056.
Shertzer
H G
HG
Berger
M L
ML
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004128:Dimethylnitrosamine / Q000633:toxicity*; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D008297:Male; D008741:Methyl Methanesulfonate / Q000633:toxicity*; D008745:Methylation; D008769:Methylnitronitrosoguanidine / Q000633:toxicity*; D008770:Methylnitrosourea / Q000633:toxicity*; D011398:Promethazine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D008054:Lipid Peroxides; D008769:Methylnitronitrosoguanidine; D008770:Methylnitrosourea; D008741:Methyl Methanesulfonate; D011398:Promethazine; D004128:Dimethylnitrosamine