title: Species differences in kidney necrosis and DNA damage, distribution and glutathione-dependent metabolism of 1,2-dibromo-3-chloropropane (DBCP).
abstract: Species differences and mechanisms of 1,2-dibromo-3-chloropropane (DBCP) nephrotoxicity were investigated by studying DBCP renal necrosis and DNA damage, distribution and glutathione-dependent metabolism in rats, mice, hamsters and guinea pigs. Extensive renal tubular necrosis was observed in rats 48 hr after a single intraperitoneal administration (21-170 mumol/kg) of DBCP. Significantly less necrosis was found in mice and guinea pigs, whereas no renal damage was evident (less than 680 mumol/kg) in hamsters. The activation of DBCP to DNA damaging intermediates in vivo, as measured by alkaline elution of DNA isolated from kidney nuclei 60 min. after intraperitoneal injection of DBCP, was compared in all four species. Distinct DNA damage was detected in rats, mice and hamsters as early as 10 min. after administration of DBCP and within 30 min. in guinea pigs. Rats and guinea pigs showed similar sensitivity towards DBCP-induced DNA damage (extensive DNA damage greater than 21 mumol/kg DBCP), whereas in mice and hamsters a 10-50 times higher DBCP dose was needed to cause a similar degree of DNA damage. Renal DBCP concentrations at various time-points (20 min., 1, 3 and 8 hr) after intraperitoneal administration (85 mumol/kg) revealed that the initial (20 min.) DBCP concentration was substantially higher in rats and guinea pigs compared to the other two species. Furthermore, kidney elimination of DBCP occurred at a significantly lower rate in rats than in mice, hamsters and guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Environmental Medicine, National Institute of Public Health, Oslo, Norway.
authors.forename: E J
authors.initials: EJ
authors.lastname: Søderlund
authors.forename: M
authors.initials: M
authors.lastname: Låg
authors.forename: J A
authors.initials: JA
authors.lastname: Holme
authors.forename: G
authors.initials: G
authors.lastname: Brunborg
authors.forename: J G
authors.initials: JG
authors.lastname: Omichinski
authors.forename: J E
authors.initials: JE
authors.lastname: Dahl
authors.forename: S D
authors.initials: SD
authors.lastname: Nelson
authors.forename: E
authors.initials: E
authors.lastname: Dybing
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced*; D000818:Animals; D001965:Bromides / Q000378:metabolism; D006224:Cricetinae; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D006168:Guinea Pigs; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced*; D008297:Male; D051379:Mice; D009249:NADP / Q000378:metabolism; D011407:Propane / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D001965:Bromides; D009249:NADP; C007318:1,2-dibromo-3-chloropropane; D005978:Glutathione; D011407:Propane