1: Toxicol In Vitro  2002 Feb;16(1):47-54 

Effects of bacterial endotoxin (lipopolysaccharides) on survival and metabolism
of cultured precision-cut rat liver slices.

Evdokimova E, Taper H, Calderon PB.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie, Departement
des Sciences Pharmaceutiques, Universite Catholique de Louvain, Brussels,
Belgium.

The effect of bacterial endotoxin (lipopolysaccharides from Escherichia coli,
LPS) on cellular metabolism and drug biotransformation was studied in
precision-cut rat liver slices (PCLS). Xenobiotic metabolism by PCLS was
assessed by measuring phase I (midazolam hydroxylation) and phase II
(paracetamol conjugates) enzyme activities. Nitrites formation was used as an
indirect way to assess LPS-mediated activation of nitric oxide synthase (iNOS,
type 2). PCLS incubation with various LPS doses results in a dose-dependent
formation of nitrites. Such a nitrite formation is decreased by dexamethasone.
After incubation of PCLS for 24 h LPS addition did not increase the basal
nitrite formation, indicating that cells are not responsive any more.
Paracetamol conjugation was unaffected by LPS treatment but midazolam
hydroxylation was reduced by more than 50%. Such a loss is not due to cell
impairment since neither survival (LDH leakage) nor cellular metabolism (protein
synthesis or ATP content) were modified by LPS. Indeed, under defined
conditions, namely Williams' medium E and O(2)/CO(2) (95:5), PCLS maintained
both ATP and GSH levels and the capacity of hepatocytes to synthesize proteins.
In conclusion, the in vitro model of PCLS reproduces the inhibitory effect of
LPS on a CYP3A-dependent activity, allowing a mechanistic approach to study
cell-cell interactions.

PMID: 11812639 [PubMed - indexed for MEDLINE]