Cytotoxicity of ortho-phenylphenol in isolated rat hepatocytes.
The effects of ortho-phenylphenol (OPP) and its metabolites, phenyl-hydroquinol (PHQ) and phenyl-benzoquinone (PBQ), on isolated rat hepatocytes were investigated. Addition of OPP (0.5-1.0 mM) to cells caused a dose-dependent cell death accompanied by the depletion of intracellular levels of ATP, glutathione (GSH) and protein thiols. GSH loss correlated with the formation of oxidized GSH. In addition, PHQ and especially PBQ (both at 0.5 mM) resulted in acute cell death with rapid depletion of ATP, GSH and protein thiols, and further low doses of PBQ (10-50 microM) elicited serious impairment of mitochondrial functions related to oxidative phosphorylation and Ca fluxes in isolated liver mitochondria. These results indicate that mitochondria are a target for these compounds and that OPP is itself toxic to hepatocytes even when metabolism is inhibited. The loss of cellular GSH and protein thiols accompanied by the impairment of mitochondrial function may be the main mechanisms of cytotoxicity induced by OPP and its metabolites.
Nakagawa
Y
Y
Department of Toxicology, Karolinska Institute, Stockholm, Sweden.
Moldéus
P
P
Moore
G A
GA
D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D051381:Rats; D011916:Rats, Inbred F344
D000227:Adenine Nucleotides; D001713:Biphenyl Compounds; D005659:Fungicides, Industrial; C004369:2-phenylphenol; D002118:Calcium