DNA damage and cell death induced by 1,2-dibromo-3-chloropropane (DBCP) and structural analogs in monolayer culture of rat hepatocytes: 3-aminobenzamide inhibits the toxicity of DBCP.
1,2-Dibromo-3-chloropropane (DBCP) and a number of halogenated propane analogs induced DNA damage in rat hepatocytes in vitro measured by an automated alkaline elution method. Short-term (2 hrs) cytotoxic effects of DBCP were not observed until the DBCP concentration exceeded 1 mM. The short-term cytotoxicity of all the DBCP analogs occurred in the same concentration range. Significant membrane damage, measured as cell detachment, was observed after extended exposure to lower concentrations of DBCP (100 microM) for 20 hrs. The relative, delayed cytotoxic effect of DBCP and analogs correlated with their ability to cause DNA damage. In general, the halogenated propanes with more bromines relative to chlorines were the more potent compounds. Propane analogs lacking the third halogen had little cytotoxic activity. The addition of the proposed specific poly(ADP-ribosyl)transferase inhibitor 3-aminobenzamide (3-ABA) protected against DBCP-induced cytotoxic effects and NAD+ depletion. However, 3-ABA also reduced DBCP-induced DNA damage, DBCP metabolic loss, and the formation of water soluble and covalently bound DBCP metabolites. Thus, 3-ABA may block DBCP-induced cell death by decreasing the formation of reactive DBCP-metabolites.
Holme
J A
JA
Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Brunborg
G
G
Låg
M
M
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004249:DNA Damage / Q000187:drug effects*; D004347:Drug Interactions; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D011407:Propane / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains
D001549:Benzamides; C025160:3-aminobenzamide; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; D011407:Propane