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Unusual Generation of Hydroxyl Radicals in Hepatic Copper-Metallothionein of LEC (Long-Evans Cinnamon) Rats in the Presence of Hydrogen Peroxide

https://doi.org/10.1006/bbrc.1994.1230Get rights and content

Abstract

A mutant strain of LEC rats (Long-Evans rats with a cinnamon-like coat color) develop spontaneous hepatic injury associated with severe jaundice about 4 months after birth. Recently, we obtained evidence which shows an unusual accumulation of copper (Cu) in the liver of LEC rats, followed by the finding of copper-methallothionein (Cu-MT) induction. To know the mechanism for the development of hepatitis in LEC rats, in relation to induced Cu-MT, we examined whether the generation of active oxygen species is observed. When the Cu-MT was treated with H2O2, which is formed by dismutation of superoxide anion radicals or NADPH oxidases in living systems, strong ESR signals due to Cu(II) state appeared when measured at 77K. On the same system, ESR signals due to the spin trapped hydroxyl radicals were observed at room temperature when DMPO (5,5-dimethyl-pyrroline-1-oxide) was used as a spin-trapping agent. The present results suggested that Cu-MT of LEC rat has an important pathogenic role by generating hydroxyl radicals, when hydrogen peroxide is produced in cells or tissues.

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    1) In Long-Evans cinnamon (LEC) rats which have a mutation in Atp7b and suffer from hereditary hepatitis and liver cancer, Cu, Fe, and Zn concentrations are much higher than in control healthy rats, paralleled with a hepatic Cu-MT concentration that is 140 times higher than in control rats [43,44]. It was further shown that this huge amount of Cu-MT in LEC rats has an important pathogenic role by generating hydroxyl radicals when hydrogen peroxide is produced in cells through respiration [45]. LEC rats' liver is much more sensitive to chemical hepatocarcinogens than normal rats' livers [46]. (

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