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Mechanism of mitochondrial dysfunction and cytotoxicity induced by tropolones in isolated rat hepatocytes.

Abstract：

:The mechanism of mitochondrial dysfunction and toxicity induced by the tropolones, beta-thujaplicin (4-isopropyl tropolone), tropolone and tropone, has been studied in freshly isolated rat hepatocytes. Incubation of hepatocytes with beta-thujaplicin (1-4 mM) elicited a concentration and time-dependent cell killing. The toxicity was accompanied by losses of cellular ATP, total adenine nucleotides and glutathione, independently of lipid peroxidation and protein thiol oxidation. The beta-thujaplicin-induced cytotoxicity was enhanced by the pretreatment of hepatocyte suspensions with EDTA (4 mM), a hydrophilic chelator, or by incubation in Ca2+ and Mg2+-deficient Krebs-Henseleit buffer. The partition coefficient of beta-thujaplicin, which formed complex with the divalent cations in Krebs-Henseleit buffer, in n-octanol/buffer was increased either in the presence of EDTA or absence of divalent cations. Comparison of toxic effects based on cell viability and adenine nucleotide levels showed that beta-thujaplicin was more toxic than tropolone or tropone in Krebs-Henseleit buffer containing EDTA (4 mM). The addition of beta-thujaplicin to isolated hepatic mitochondria reduced state 3 respiration with NAD+-linked substrate (pyruvate plus malate) and/or with an FAD-linked substrate (succinate plus rotenone), whereas state 3 respiration of ascorbate plus tetramethyl-p-phenylenediamine (cytochrome oxidase-linked respiration) was not significantly affected by beta-thujaplicin. Further, the addition of these tropolones caused a concentration-dependent increase in the rate of state 4 oxygen consumption, indicating an uncoupling effect. These results indicate that beta-thujaplicin- and tropolone-induced cytotoxicity are associated with an acute ATP depletion via mitochondrial dysfunction related to oxidative phosphorylation and that the induction of cytotoxicity is affected by EDTA or divalent cations.

journal_name

Chem Biol Interact

journal_title

Chemico-biological interactions

authors

Nakagawa Y,Tayama K

doi

10.1016/s0009-2797(98)00078-7

subject

Has Abstract

pub_date

1998-11-06 00:00:00

pages

45-60

issue

1-2

eissn

0009-2797

issn

1872-7786

pii

S0009-2797(98)00078-7

journal_volume

116

pub_type

杂志文章

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Mechanism of mitochondrial dysfunction and cytotoxicity induced by tropolones in isolated rat hepatocytes.