The role of oxidative and conjugative pathways in the activation of 1,2-dibromo-3-chloropropane to DNA-damaging products in rat testicular cells.
The ability of 1,2-dibromo-3-chloropropane (DBCP), several methylated analogs of DBCP and perdeuterated DBCP (DBCP-D5) to cause DNA damage in isolated testicular cells from rats was measured by the alkaline elution technique. Of the methylated analogs studied, only the C3-methyl analog was capable of causing significant DNA damage at concentrations of 0-50 microM. In both time- (0-60 min) and concentration- (0-10 microM) dependent experiments, the testicular cell DNA damage caused by the perdeuterated analog of DBCP closely mimicked the damage resulting from DBCP itself. The lack of an isotope effect between DBCP-D5 and DBCP strongly suggests that metabolism via a cytochrome P-450-dependent pathway is not involved in the DNA-damaging effects of DBCP in rat testicular cells. In contrast, preincubation for 1 hr with diethylmaleate (DEM) inhibited DBCP-induced (10 microM) DNA damage in a concentration-dependent manner (0-500 microM DEM). The decrease in testicular DNA damage was proportional to the decrease in cellular nonprotein sulfhydryl levels. Similarly, it was shown that 1,2-dibromoethane (EDB), a structurally related halogenated alkane, produced DNA damage in isolated testicular cells in both a time- (0-60 min) and concentration- (0-600 microM) dependent fashion. The DNA damage produced by EDB (600 microM) was also inhibited by pretreatment of testicular cells with DEM (1 mM). The testicular genotoxicity induced by EDB is thought to involve its initial conjugation to glutathione and the subsequent formation of a reactive episulfonium ion. The data presented indicate that similar events may be occurring in DBCP-induced DNA damage in rat testicular cells.
Omichinski
J G
JG
Department of Toxicology, National Institute of Public Health, Oslo, Norway.
Brunborg
G
G
Holme
J A
JA
Søderlund
E J
EJ
Nelson
S D
SD
Dybing
E
E
D000818:Animals; D001711:Biotransformation; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008745:Methylation; D010084:Oxidation-Reduction; D011407:Propane / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000187:drug effects*
D008298:Maleates; D004247:DNA; C007318:1,2-dibromo-3-chloropropane; C014476:diethyl maleate; D005978:Glutathione; D011407:Propane