Different mechanisms are involved in DNA damage, bacterial mutagenicity and cytotoxicity induced by 1,2-dibromo-3-chloropropane in suspensions of rat liver cells.
1,2-Dibromo-3-chloropropane (DBCP) induced DNA damage, measured by an automated alkaline elution method, in suspensions of rat liver parenchymal cells at low concentrations (1-10 microM). At much higher concentrations (0.5-2.5 mM), DBCP was metabolized to products that were mutagenic to Salmonella typhimurium TA100 co-incubated with the liver cells. At these higher concentrations a marked depletion of cellular glutathione was seen and at 2.5 mM DBCP was cytotoxic. Perdeuterated DBCP (D5-DBCP) caused less DNA damage in the liver cells than DBCP, most likely because of decrease in cytochrome P-450 dependent metabolism. A more pronounced decrease in mutagenicity occurred with D5-DBCP compared to DBCP, whereas the two compounds were equally cytotoxic. Preincubation of the liver cells with diethylmaleate or buthionine sulfoximine, to lower cellular levels of glutathione, decreased DBCP induced DNA damage. The decrease in DNA damage was proportional to the decrease in cellular glutathione levels. In contrast, diethylmaleate enhanced DBCP-induced bacterial mutagenicity and cellular cytotoxicity. The cytotoxic effect could be partly blocked by addition of ascorbate. From the data presented we suggest that: (i) cytochrome P-450 dependent oxidation as well as glutathione conjugation are involved in DBCP induced DNA damage, (ii) cytochrome P-450 dependent oxidation leads to formation of products mutagenic to bacteria and (iii) the cytotoxicity induced by DBCP in the liver cells in vitro is caused by oxidative damage following glutathione depletion and/or direct membrane damage.
Holme
J A
JA
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Søderlund
E J
EJ
Brunborg
G
G
Omichinski
J G
JG
Bekkedal
K
K
Trygg
B
B
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D001711:Biotransformation; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D009152:Mutagenicity Tests; D009154:Mutation / Q000187:drug effects*; D011407:Propane / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013997:Time Factors
D008298:Maleates; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; C014476:diethyl maleate; D005978:Glutathione; D011407:Propane