Ethanol-enhanced cytotoxicity of alkylating agents.
BACKGROUND
Although ethanol itself is not genotoxic, chronic alcohol consumption increases the risk of neoplastic disease. The mechanism by which ethanol exerts a cocarcinogenic effect is not well established, and the aim of this study was to determine whether exposure to ethanol increased the cytotoxicity of known carcinogens.


METHODS
To assess cell survival, the ability of Chinese hamster A10 cells, which express alcohol dehydrogenase, to form colonies was determined after exposure to ethanol and other substances, including both genotoxicants and non-DNA-reactive cytotoxic agents.


RESULTS
1-Methyl-3-nitro-1-nitrosoguanidine (MNNG) is an alkylating agent that forms covalent bonds with DNA. The cytotoxicity of MNNG at concentrations of 0.17 to 0.68 microM was markedly enhanced when cells were also treated with 50 mM ethanol. When combined with 0.34 microM MNNG, concentrations of ethanol as low as 2 mM exacerbated the toxicity of this alkylating agent. When these experiments were repeated in the presence of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, pretreatment with ethanol did not affect the toxicity of MNNG. When ethanol treatment was combined with exposure to other carcinogens, as well as agents that do not directly damage DNA, the cytotoxicity of the DNA-reactive agents 4-nitroquinoline-N-oxide, mitomycin C, and 6-chloro-9-(3-[2-chloroethyl]aminopropylamino)-2-methoxyacridine was modestly enhanced, and that of a second alkylating agent, ethyl methanesulfonate, was markedly increased.


CONCLUSIONS
The results are consistent with impairment of DNA repair processes, particularly base excision repair, by acetaldehyde, as a mechanism by which ethanol increases the genotoxicity of certain genotoxic agents.
Couch
David B
DB
Department of Pharmacology and Toxicology, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA. dcouch@pharmacology.umsmed.edu
Baker
Rodney C
RC
D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002492:Central Nervous System Depressants / Q000633:toxicity*; D006224:Cricetinae; D004357:Drug Synergism; D000431:Ethanol / Q000633:toxicity*; D008769:Methylnitronitrosoguanidine / Q000633:toxicity
D000477:Alkylating Agents; D002492:Central Nervous System Depressants; D008769:Methylnitronitrosoguanidine; D000431:Ethanol; D000426:Alcohol Dehydrogenase