Pentachlorobutadienyl-l-cysteine uncouples oxidative phosphorylation by dissipating the proton gradient

Rick G. Schnellmann, Theresa J. Cross, Edward A. Lock

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

A very early event in the toxicity of pentachlorobutadienyl-l-cysteine (PCBC) to rabbit renal proximal tubules is uncoupling of oxidative phosphorylation (R. G. Schnellmann, E. A. Lock, and L. J. Mandel (1986), Toxicologist 6, 176; (1987), Toxicol. Appl. Pharmacol. 90, 521). The mechanism of PCBC uncoupling of mitochondrial oxidative phosphorylation has been investigated using isolated rabbit renal cortical mitochondria (RCM). PCBC increased state 4 respiration of RCM respiring on pyruvate/malate or succinate in a concentration (10-100 μm)- and time (1-5 min)-dependent manner. PCBC also increased state 4 respiration in the presence of oligomycin, an inhibitor of F0F1-ATPase. The effect of PCBC on mitochondrial proton permeability was determined by measuring passive mitochondrial swelling. After a 2-min exposure to PCBC, RCM swelled when placed in NH4Cl or NaCl, but not KCl or sucrose. The protonophore carbonyl cyanide p-trifluoromethoxyphenyl hydrazone (FCCP) (1 μm) produced similar effects. After 5 min, RCM swelled when placed in NH4Cl, NaCl, or KCl, but not in sucrose. Aminooxyacetic acid, an inhibitor of cysteine conjugate β-lyase, blocked the effects of PCBC on respiration, indicating that PCBC can be metabolized by RCM to produce RCM toxicity. These results show that PCBC initially uncouples oxidative phosphorylation by dissipating the proton gradient. Subsequently, additional ion permeabilities occur. These results are in complete agreement with previous observations in rabbit renal proximal tubule suspensions.

Original languageEnglish (US)
Pages (from-to)498-505
Number of pages8
JournalToxicology and Applied Pharmacology
Volume100
Issue number3
DOIs
StatePublished - Sep 15 1989
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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