TITLE:
Repression of oxidative stress/reactive metabolite regulated gene expression is associated with conversion of carbamazepine into a hepatotoxicant in LPS and DSS rat models
AUTHORS:
Angelique M. Leone, Erin Saleh, S. Jim Proctor, Michael F. Kelley, L. Mark Kao, Lynn Varacallo, Peter Taggart, Jean McCarthy, Monica Singer, Michael McMillian
KEYWORDS:
Hepatotoxicity; Gene Expression; Oxidative Stress/Reactive Metabolites (OS/RM); LPS; DSS
JOURNAL NAME:
Advances in Bioscience and Biotechnology,
Vol.5 No.3,
February
10,
2014
ABSTRACT:
Idiosyncratic hepatotoxicity accounts for many drug
failures in the clinic and is a leading cause for black-boxed and withdrawn
drugs. This toxicity has proven difficult to predict preclinically, but correlates
with oxidative stress/reactive metabolites (OS/RM). As noted previously for antiepileptic compounds, many
drugs causing idiosyncratic adverse drug effects are detected by OS/RM
gene expression responses in the rat. In the present study, two immune
activation models, low dose lipopolysaccharide (1 mg/kg IV) and 5% dextran
sulphate sodium (DSS) in drinking water, were examined to determine if either
would convert the non-toxic idiosyncratic toxicant carbamazepine (225 mg/kg)
into a rat hepatotoxicant at 24 hours. Using the low dose LPS model, about 1/3
of the carbamazepine-treated rats either showed robust ALT and AST elevations
with histopathological evidence of hepatotoxicity, or died. Rats in this
LPS/carbamazepine group were subdivided based on ALT values into
non-responders, responders or robust responders. Whereas most
carbamazepine-induced mRNAs were repressed by LPS across all rats in this
group, the OS/ RM genes aflatoxin aldehyde reductase (Afar) and glutathione
transferase Ya (Gstya) were repressed only in the robust responder subgroup; it
is unclear whether repression of these genes contributes to or results from
hepatotoxicity. The OS/RM gene microsomal epoxide hydrolase (mEphx) showed repression
across all rats. NAD(P)H: menadione oxidoreductase (Nmor) is an
OS/RM-responsive gene that is also induced by LPS, confounding interpretation
of its changes. After pretreatment with 5% DSS at 24 hours or for 5 days,
using a protocol that reportedly produces increased endotoxin absorption,
carbamazepine was not converted to a hepatototoxicant in any rats. Instead, DSS
produced a pronounced (2- to 6-fold) and selective potentiation of
carbamazepine induction of OS/RM-responsive mRNAs. The lack of repressive
effects of DSS on these mRNAs or in converting carbamazepine to a
hepatotoxicant was not due to desensitization of endotoxin responses since LPS
was at least as effective when administered to DSS-pretreated rats. OS/RM
gene repression may contribute to development of hepatotoxicity of
carbamazepine in immune activation models.