The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the
liver from a number of toxicants that require biotransformation to eli
cit toxicity (i.e. 1,2-dichlorobenzene and CCl4), as well as compounds
that do not (i.e. cadmium chloride and beryllium sulfate). The mechan
ism of this protection is thought to result from reduced secretion of
inflammatory and cytotoxic products from Kupffer cells (KC). However,
since other lanthanides have been shown to decrease cytochrome P450 (P
450) activity, the following studies were designed to determine if GdC
l3 pretreatment alters hepatic P450 levels or activity. The toxicologi
cal relevance of GdCl3-mediated alterations in P450 activity was also
estimated by determining the effect of GdCl3 pretreatment on the susce
ptibility of primary cultured hepatocytes to CCl4 and cadmium chloride
(CdCl2). Male and female Sprague-Dawley rats were given GdCl3 (i.v.,
10 mg/kg). Twenty-four hours later, livers were either processed for p
reparation of microsomes or for primary cultures of hepatocytes. Gadol
inium chloride treatment reduced total hepatic microsomal P450 as well
as aniline hydroxylase activity by approximately 30% in males and 20%
in females. In hepatocytes isolated from rats pretreated with GdCl3,
the toxicity caused by CCl4, but not CdCl2 was reduced. Interestingly,
when GdCl3 was administered in vitro to microsomes, there was no effe
ct on either the microsomal P450 difference spectra or p-hydroxylation
of aniline. However, when GdCl3 was incubated with isolated hepatocyt
es, the cytotoxicity of CCl4 (but not CdCl2) was partially attenuated.
These results suggest that, in addition to its inhibitory effects on
KC, GdCl3 produces other effects which may alter the susceptibility of
hepatocytes to toxicity caused by certain chemicals. (C) 1997 Elsevie
r Science Ireland Ltd.