Formation of Quinonoid-Derived Protein Adducts in the Liver and Brain of Sprague-Dawley Rats Treated with 2,2',5,5'-Tetrachlorobiphenyl

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• 作者：Po-Hsiung Lin ; Ramiah Sangaiah ; Asoka Ranasinghe ; Patricia B. Upton ; David K. La ; Avram Gold ; and James A. Swenberg
• 刊名：Chemical Research in Toxicology
• 出版年：2000
• 出版时间：August 2000
• 年：2000
• 卷：13
• 期：8
• 页码：710 - 718
• 全文大小：300K
• 年卷期：v.13,no.8(August 2000)
• ISSN：1520-5010

文摘

A possible role for metabolic activation of 2,2',5,5'-tetrachlorobiphenyl (TCB) to quinonoidmetabolites was investigated in vitro in rat liver microsomes and in vivo in male Sprague-Dawley rats. Incubation of TCB with phenobarbital-induced rat liver microsomes resulted inmetabolism of TCB to 3-hydroxy-TCB (3-OH-TCB) and 3,4-dihydroxy-TCB (3,4-diOH-TCB),which were further oxidized to form a reactive intermediate that bound to liver proteins. Thepredominant species observed in the Raney nickel assay for cysteinyl adducts was identifiedas 3,4-diOH-TCB, consistent with an adduct having the structure 5-cysteinyl-3,6-dichloro-4-(2',5'-dichlorophenyl)-1,2-benzoquinone. This adduct may arise via the Michael addition of thesulfhydryl group of cysteine to 3,6-dichloro-4-(2',5'-dichlorophenyl)-1,2-benzoquinone (Cl₄PhBQ).Metabolism of 3-OH-TCB by phenobarbital-induced microsomes in the presence of eitherNADPH or cumene hydroperoxide as a cofactor resulted in the formation of adducts. Dose-dependent formation of cysteinyl adducts was observed in liver cytosolic protein from ratstreated with a single dose of TCB (0-200 mg/kg) by gavage. By regression analysis, the TCBadducts decayed with a half-life of 2.03 ± 0.131 days (mean ± SE), which is ~2.5-fold shorterthan the endogenous half-life for liver cytosolic protein in rat liver, suggesting adduct instability.Saturable formation of TCB adducts was observed in liver cytosolic protein of rats receivingmultiple doses of TCB over 5 days. The levels of Cl₄PhBQ-derived adducts were 2.1-fold greaterthan the estimated steady-state levels predicted by the single-dose treatment [97.7 ± 13.2 vs45.7 ± 3.73 (pmol/g)/(mg/kg of body weight)], suggesting induction of metabolism. A singlecysteinyl adduct, inferred to be 5-cysteinyl-3,6-dichloro-4-(2',5'-dichlorophenyl)-1,2-benzoquinone, was detected in brain cytosolic protein of rats treated with multiple doses of TCBwith levels of 15.2 (pmol/g)/(mg/kg of body weight). Implied involvement of a reactive quinonein the liver and brain of TCB-treated rats supports the idea that quinonoid metabolites maybe important contributors to PCB-derived oxidative damage to genomic DNA.