Gf. Stephenson et al., COPPER-METALLOTHIONEIN FROM THE TOXIC MILK MUTANT MOUSE ENHANCES LIPID-PEROXIDATION INITIATED BY AN ORGANIC HYDROPEROXIDE, Toxicology and applied pharmacology, 125(1), 1994, pp. 90-96
The toxic milk mutation is an autosomal recessive mutation found in an
inbred C57BL/6J strain of mice which results in an excessive hepatic
accumulation of copper (Cu), mostly associated with metallothionein (M
T). The possible toxicological significance of elevated levels of hepa
tic copper-metallothionein (Cu-MT) was assessed. The effects of Cu-MT
on lipid peroxidation (LP) initiated by an organic peroxide were inves
tigated in an in vitro rat liver microsomal incubation system. Additio
n of Cu-MT (3 mu M) could significantly enhance (100%) LP induced by a
ddition of tertiary-butyl hydroperoxide (t-BHP, 0.1 mM). Similar incub
ations of Cu-MT in the absence of t-BHP showed negligible LP. Addition
of copper sulfate at high concentrations (100 mu M) also increased t-
BHP induced LP, but the enhancement was less pronounced than observed
with Cu-MT addition. Chelation of copper with bovine serum albumin and
triethylenetetramine tetrahydrochloride eliminated the enhancement of
LP by Cu-MT. Evidence is provided on degradation of MT and release of
free Cu in the incubation system. Additions of deferoxamine were also
found to prevent LP. Therefore, chelatable Cu, released from Cu-MT, m
ay be responsible for the enhancement of the iron-dependent LP in this
system but Cu-MT alone in the absence of iron cannot initiate LP. The
se in vitro results suggest that conditions resulting in high cellular
levels of Cu-MT may exhibit a predisposition to oxidative stress. (C)
1994 Academic Press, Inc.