当前位置： SCI文献检索 > TOXICOLOGY AND APPLIED PHARMACOLOGY期刊下所有文献 > Renal necrosis and DNA damage caused by selectively deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat.

Renal necrosis and DNA damage caused by selectively deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat.

Abstract：

: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.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Omichinski JG,Brunborg G,Søderlund EJ,Dahl JE,Bausano JA,Holme JA,Nelson SD,Dybing E

doi

10.1016/0041-008x(87)90058-5

subject

Has Abstract

pub_date

1987-12-01 00:00:00

pages

358-70

issue

eissn

0041-008X

issn

1096-0333

journal_volume

pub_type

杂志文章

在线工具

Renal necrosis and DNA damage caused by selectively deuterated and methylated analogs of 1,2-dibromo-3-chloropropane in the rat.