Biotransformation and cytotoxicity of a brominated flame retardant, tetrabromobisphenol A, and its analogues in rat hepatocytes.
The metabolism and cytotoxic effects of tetrabromobisphenol A (TBBPA), a phenolic flame retardant, and its analogues were studied in freshly isolated rat hepatocytes and isolated hepatic mitochondria, respectively. The exposure of hepatocytes to TBBPA caused not only concentration (0.25-1.0 mM)- and time- (0-3 h) dependent cell death accompanied by the loss of cellular ATP, adenine nucleotide pools, reduced glutathione, and protein thiols, but also the accumulation of oxidized glutathione and malondialdehyde, indicating lipid peroxidation. TBBPA at a weakly toxic level (0.25 mM) was metabolized to monoglucuronide and monosulfate conjugates: the amounts of glucuronide rather than sulfate conjugate predominantly increased, accompanied by a loss of the parent compound, with time. In comparative effects based on cell viability, mitochondrial membrane potential and some toxic parameters, bisphenol A (BPA) was less toxic than TBBPA and tetrachlorobisphenol A (TCBPA), which are not significant differences in these parameters. In mitochondria isolated from rat liver, TBBPA and TCBPA caused an increase in the rate of State 4 oxygen consumption in the presence of succinate, indicating an uncoupling effect and a decrease in the rate of State 3 oxygen consumption in a concentration-dependent manner (5-25 microM). Taken collectively, our results indicate that (i) mitochondria are target organelles for TBBPA, which elicits cytotoxicity through mitochondrial dysfunction related to oxidative phosphorylation at an early stage and subsequently lipid peroxidation at a later stage; and (ii) the toxicity of TBBPA and TCBPA is greater than that of BPA, suggesting the participation of halogen atoms such as bromine and chlorine in the toxicity.
Nakagawa
Y
Y
Division of Pharmacology, Tokyo Metropolitan Institute of Public Health, Japan. Yoshio_1_Nakagawa@member.metro.tokyo.jp
Suzuki
T
T
Ishii
H
H
Ogata
A
A
D000818:Animals; D002478:Cells, Cultured; D005411:Flame Retardants / Q000493:pharmacokinetics* / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011075:Polybrominated Biphenyls / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344
D005411:Flame Retardants; D011075:Polybrominated Biphenyls; C020806:tetrabromobisphenol A