Role of mitochondrial membrane permeability transition in p-hydroxybenzoate ester-induced cytotoxicity in rat hepatocytes.
The relationship between mitochondrial membrane permeability transition (MPT) and the toxic effects of the alkyl esters of p-hydroxybenzoic acid (parabens) has been studied in mitochondria and hepatocytes isolated from rat liver. MPT has been proposed as a common final pathway in acute cell death through mitochondrial dysfunction. In isolated mitochondria, propyl-paraben (0.1 to 0.5 mM) in the presence of Ca2+ (50 microM) elicited a concentration-dependent induction of mitochondrial swelling dependent on MPT. This was prevented by pretreatment with a specific inhibitor of MPT, cyclosporin A (0.2 microM). For the other parabens tested, the induction of MPT depended on the relative elongation of alkyl side-chains in their molecular structure and was associated with the partition coefficients. In contrast, the induction caused by p-hydroxybenzoic acid was more potent than that of methyl- or ethyl-paraben. The pretreatment of freshly isolated hepatocytes with cyclosporin A (5 microM) and trifluoperazine (10 microM), which inhibit MPT in a synergistic manner, partially but not completely prevented propyl-paraben (1 mM; plus diazinon, 100 microM)-induced cell death, ATP loss, and decreased mitochondrial membrane potential. These results suggest that the onset of paraben-induced cytotoxicity is linked to mitochondrial failure dependent upon induction of MPT accompanied by the mitochondrial depolarization and depletion of cellular ATP through uncoupling of oxidative phosphorylation.
Nakagawa
Y
Y
Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan. yoshio@tokyo-eiken.go.jp
Moore
G
G
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects* / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D010226:Parabens / Q000378:metabolism / Q000633:toxicity*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344
D010226:Parabens