Selectively deuterated and methylated analogs of the nematocide
1,2-dibromo-3-chloropropane (
DBCP) were compared to
DBCP in causing acute renal damage in rats. All of the six deuterated analogs tested at 340 mumol/kg, including the perdeutero compound, failed to significantly alter the kidney
necrosis observed at 48 hr compared to
DBCP. Furthermore, when the perdeutero analog was administered at several doses (42.5, 85, 170, and 340 mumol/kg), it caused kidney damage that was not significantly different than that caused by an equivalent molar dose of nondeuterated
DBCP. Of the five methylated analogs tested at 170 and 340 mumol/kg, only C3-methyl-DBCP and 1,2-dibromo-4-chlorobutane caused nephrotoxicity. The C2-methyl-, C1-dimethyl-, and C2-methyl-DBCP analogs failed to cause renal
necrosis determined 48 hr after dosing. In distribution studies
DBCP, perdeutero-
DBCP, and all the methylated analogs were found to concentrate in the kidney approximately 25 times relative to plasma 1 hr after administration.
DBCP at doses of 4.3 mumol/kg and higher caused DNA damage in the kidney as early as 10 min after administration, as measured by alkaline elution of
DNA from isolated kidney nuclear preparations. Perdeuteration did not decrease the
DNA damaging effect of
DBCP. The ability of the methylated
DBCP analogs to induce renal DNA damage correlated with their necrogenic potential. Experiments using pretreatments that are known to decrease the nephrotoxicity caused by
glutathione and
cysteine conjugates of several halogenated
alkenes were conducted to examine the effect of these pretreatments on
DBCP-induced nephrotoxicity.
Probenecid, L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic
acid (AT-125) and
aminooxyacetic acid did not significantly alter renal
necrosis or DNA damage induced by
DBCP. Based on the absence of any significant
isotope effects with the predeutero-
DBCP analog, it appears that breaking of a
carbon-hydrogen bond is not the rate-limiting step in
DBCP-induced nephrotoxicity. Studies with the methylated
DBCP analogs indicate that a vicinal dibromo ethyl group must minimally be present for nephrotoxic potential. Furthermore, it seems unlikely that metabolism by renal
cysteine conjugate beta-lyase is rate-limiting for
DBCP nephrotoxicity.