F. Moritz et al., IMPACT OF CEPHALORIDINE ON GLUTATHIONE AND RELATED ENZYMES - COMPARISONS OF IN-VIVO AND IN-VITRO RAT MODELS, Archives of toxicology, 70(2), 1995, pp. 104-111
The aim of this study was to investigate the early effects of cephalor
idine (CPH) on glutathione-dependent phase II detoxification in the ra
t proximal tubular cell and to find an in vitro alternative to the in
vivo model. The in vivo study was conducted in three groups of rats wh
ich received CPH at doses of 250, 500 or 750 mg/kg per day for 3 days,
while another group received 500 mg/kg as a single dose. For the in v
itro study, rat renal proximal tubular cultured cells were exposed to
CPH at concentrations of 0.3, 0.6, 1, 1.7 mM for 24, 48 and 72 h. Glut
athione-dependent detoxification was evaluated in vivo and in vitro on
the basis of total intracellular glutathione (GSH), glutathione S-tra
nsferase (GST) and glutathione peroxidase (GPX). Glutathione reductase
(GRED) and GST mRNA levels were also determined. Results of in vivo a
nd in vitro models were comparable in terms of the early increase of G
SH, GST and GRED. This increase had a bell-shaped dose-response with a
maximum at 500 mg/kg in vivo and 1 mM in vitro. Beyond these doses, G
SH and its dependent enzyme levels decreased, associated with cytotoxi
city in vitro and renal insufficiency in vivo. The increased GST activ
ity was associated with an increased level of GST7 in vivo and a marke
dly increased level of GST1-2 in vitro. We concluded that the in vitro
model can be used as an alternative to animal experimentation to stud
y glutathione-dependent detoxication. Low cytotoxic doses of CPH induc
ed an early increase of glutathione phase II-dependent detoxification
enzymes.