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Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates.

Abstract：

:The role of lipid peroxidation in the cell death produced by the haloalkene cysteine conjugates S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine (PCBC), S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFEC), and S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine (CTFC) was investigated using a well-defined suspension of rabbit renal proximal tubules. PCBC, DCVC, TFEC, and CTFC at a concentration of 25 microM caused renal proximal tubular death (measured by lactate dehydrogenase release) in a time-dependent (2-6 hr) manner and increased tubular malondialdehyde (MDA) formation prior to and during cell death (1-6 hr). The antioxidants butylated hydroxytoluene (BHT) (25 microM) and N,N'-diphenyl-1,4-phenylenediamine (DPPD) (50 microM) and the iron chelator deferoxamine (1 mM) blocked the increase in MDA formation produced by these four compounds. BHT and deferoxamine delayed PCBC-, DCVC-, and CTFC-induced cell death but had no effect on the overall extent of cell death. BHT and deferoxamine had no effect on TFEC-induced cell death. DPPD had effects similar to those of deferoxamine on DCVC- and CTFC-induced cell death, but, unlike deferoxamine, DPPD significantly reduced PCBC- and TFEC-induced cell death. This difference in the effect of DPPD may not be related to its effects as an antioxidant. The antioxidant, putative cellular phospholipase inhibitor and calmodulin antagonist, chlorpromazine (100 microM), blocked the increase in MDA formation and after 6 hr decreased by 50% the degree of cell death produced by PCBC, DCVC, TFEC, and CTFC. Furthermore, chlorpromazine could be added 1 or 2 hr after DCVC or PCBC and still provide the same degree of protection. The enhanced protection with chlorpromazine, in relation to deferoxamine and BHT, may be related to its actions as a phospholipase inhibitor and/or calmodulin antagonist. These results show that iron-dependent lipid peroxidation plays a role in PCBC-, DCVC-, and CTFC-induced rabbit renal proximal tubule cell death. In contrast, iron-dependent lipid peroxidation plays no role in TFEC-induced proximal tubule cell death. These observations suggest that mechanisms other than peroxidative damage may predominate in the cell death produced by these four compounds.

journal_name

Toxicol Appl Pharmacol

journal_title

Toxicology and applied pharmacology

authors

Groves CE,Lock EA,Schnellmann RG

doi

10.1016/0041-008x(91)90330-h

subject

Has Abstract

pub_date

1991-01-01 00:00:00

pages

54-62

issue

eissn

0041-008X

issn

1096-0333

journal_volume

107

pub_type

杂志文章

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Role of lipid peroxidation in renal proximal tubule cell death induced by haloalkene cysteine conjugates.