Document Detail

Mechanism of p-hydroxybenzoate ester-induced mitochondrial dysfunction and cytotoxicity in isolated rat hepatocytes.
MedLine Citation:
PMID:  9714309     Owner:  NLM     Status:  MEDLINE    
The relationship between the metabolism and the cytotoxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in freshly isolated rat hepatocytes. Incubation of hepatocytes with propyl-paraben (0.5 to 2.0 mM) elicited a concentration- and time-dependent cell death that was enhanced when enzymatic hydrolysis of propyl-paraben to p-hydroxybenzoic acid was inhibited by a carboxylesterase inhibitor, diazinon. The cytotoxicity was accompanied by losses of cellular ATP, total adenine nucleotide pools, and reduced glutathione, independently of lipid peroxidation and protein thiol oxidation. In the comparative toxic effects based on cell viability, ATP level, and rhodamine 123 retention, butyl- and isobutyl-parabens were more toxic than propyl- and isopropyl-parabens, and ethyl- and methyl-parabens and p-hydroxybenzoic acid were less toxic than propyl-paraben. The addition of propyl-paraben to isolated hepatic mitochondria reduced state 3 respiration with NAD+-linked substrates (pyruvate plus malate) and/or with an FAD-linked substrate (succinate plus rotenone), whereas state 3 respiration with ascorbate plus tetramethyl-p-phenylenediamine (cytochrome oxidase-linked respiration) was not affected significantly by propyl-paraben. Further, the addition of these parabens caused a concentration-dependent increase in the rate of state 4 oxygen consumption, indicating an uncoupling effect. The rate of state 3 oxygen consumption was inhibited by propyl-paraben, butyl-paraben, and their chain isomers. These results indicate that a) propyl-paraben-induced cytotoxicity is mediated by the parent compound rather than by its metabolite p-hydroxybenzoic acid; b) the toxicity is associated with ATP depletion via impairment of mitochondrial function related to membrane potential and/or oxidative phosphorylation; and c) the toxic potency of parabens to hepatocytes or mitochondria depends on the relative elongation of alkyl side-chains esterified to the carboxyl group of p-hydroxybenzoic acid.
Y Nakagawa; P Moldéus
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
Title:  Biochemical pharmacology     Volume:  55     ISSN:  0006-2952     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  1998 Jun 
Date Detail:
Created Date:  1998-08-31     Completed Date:  1998-08-31     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1907-14     Citation Subset:  IM    
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan.
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MeSH Terms
Adenine Nucleotides / metabolism
Cell Death / drug effects
Cell Respiration / drug effects
Food Preservatives / metabolism,  toxicity*
Liver / cytology,  drug effects*,  metabolism,  ultrastructure
Membrane Potentials / drug effects
Mitochondria, Liver / drug effects*,  metabolism
Parabens / metabolism,  toxicity*
Preservatives, Pharmaceutical / toxicity*
Rats, Inbred F344
Reg. No./Substance:
0/Adenine Nucleotides; 0/Food Preservatives; 0/Parabens; 0/Preservatives, Pharmaceutical

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