Cytotoxic effects of biphenyl and hydroxybiphenyls on isolated rat hepatocytes

Abstract

The cytotoxic effects of biphenyl (BP) and its hydroxylated derivatives, o-phenylphenol (OPP), m-phenylphenol (MPP), p-phenylphenol (PPP), 2-biphenylyl glycidyl ether (OPP-epoxide), phenyl-hydroquinone (PHQ), o,o'-biphenol (o,o'-BPol) and p,p'-biphenol (p,p'-BPol), were investigated in freshly isolated rat hepatocytes. OPP, MPP and PPP, at concentration of 0.75 mM, resulted in the loss of intracellular ATP, glutathione (GSH) and protein thiols, causing cell death. OPP-epoxide and BP were less toxic than the OPP isomers. MPP or PPP compared with OPP caused serious impairments in oxidative phosphorylation in mitochondria isolated from rat liver. PHQ (0.75 mM) caused a rapid loss of intracellular ATP which preceded the onset of cell death. PHQ was more toxic than o,o'-BPol or p,p'-BPol. PHQ dissolved in Krebs-Henseleit buffer without hepatocytes was rapidly converted to its corresponding quinone, phenyl-benzoquinone. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediates. These results indicate that the addition of a hydroxyl group to the aromatic ring of BP enhances BP-induced cytotoxicity and that the mitochondria are a common target of the OPP isomers and other BP derivatives. In addition, the para- or meta-hydroxyl groups rather than the ortho-hydroxyl group increase the toxicity. The cytotoxicity produced by PHQ depends on the rate of formation of reactive intermediate(s) such as phenyl-benzoquinone.