Aroclor 1254 inhibits the mitochondrial permeability transition and release of cytochrome c: a possible mechanism for its in vivo toxicity.
The mitochondrial permeability transition (MPT) occurs in several forms of necrotic cell death induced by various insults, including oxidative stress, ischemia/reperfusion injury Ca(2+)-ionophore toxicity, and apoptosis. In fact, the release of an apoptogenic factor such as cytochrome c is often associated with the opening of the transition pore. The present study shows that Aroclor 1254, a mixture of polychlorinated biphenyls that was banned in the U.S. in 1977 but is still present in the environment, inhibits the MPT in a dose-dependent manner in a concentration range of 1 to 25 nmol/mg protein. The compound prevents key phenomena associated with the MPT, including colloid-osmotic swelling, the collapse of membrane potential, nonspecific bidirectional traffic of solutes through the transition pore, and the oxidation of pyridine nucleotides. In contrast, Aroclor 1254 does not inhibit uptake of Ca(2+) or P(i). The effects of Aroclor 1254 are evident both in sucrose-based media and in saline and are observed when the compound is added before the opening of the pore. Aroclor 1254 prevents MPT induction provoked by a variety of agents, including phosphate, menadione, tert-butylhydroperoxide, and atractyloside. Aroclor 1254 also inhibits the specific release of cytochrome c, a correlate of MPT induction. These effects reveal a possible toxicological mechanism of action of this compound. The possibility that its effect on mitochondrial function is linked to its action as a tumor promoter is discussed.
Salvi
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M
Dipartimento di Chimica Biologica, Centro delle Biomembrane del CNR, Università di Padova, Via G. Colombo 3, Padua, 35121, Italy.
Toninello
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D020111:Chlorodiphenyl (54% Chlorine) / Q000494:pharmacology*; D003574:Cytochrome c Group / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology*; D008933:Mitochondrial Swelling / Q000187:drug effects; D010084:Oxidation-Reduction; D010539:Permeability; D011725:Pyridines / Q000378:metabolism; D051381:Rats
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D011725:Pyridines; D020111:Chlorodiphenyl (54% Chlorine); D002118:Calcium