SPECIES-DIFFERENCES IN KIDNEY NECROSIS AND DNA DAMAGE, DISTRIBUTION AND GLUTATHIONE-DEPENDENT METABOLISM OF 1,2-DIBROMO-3-CHLOROPROPANE (DBCP)

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 μmol/kg) of DBCP. Significantly less necrosis was found in mice and guinea pigs, whereas no renal damage was evident (<680 μmol/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 >21 μmol/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 μmol/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. Cytosols from all four species debrominated DBCP at appreciable rates in the presence of glutathione (GSH), with kidney preparations from rats and guinea pigs being approximately two to three times more active than those from mice and hamsters. The present findings strengthen the hypothesis that DNA damage may be an initial event in DBCP organ toxicity. The extent and persistence of the DNA damage must, however, exceed a critical value to cause cell death. The high initial renal concentration of DBCP, its relatively long half‐life in the kidney and the ability of the kidney to activate DBCP in the presence of GSH all contribute to the high susceptibility of the rat kidney to DBCP‐induced nephrotoxicity. 1990 Nordic Pharmacological Society