Abstract Number: 1008
TYPE 2 DIABETIC MICE ARE PROTECTED FROM ACETAMINOPHEN HEPATOTOXICITY
S.P.Sawant1; A.V.Dnyanmote1; M.S.Mitra1;
J.Chilakapati1; J.R.Latendresse2; H.M.Mehendale1.
1. Dept.of Toxicology, Univ. of Louisiana Monroe, Monroe, LA; 2. NCTR, Jefferson,
AR.
Type 2 diabetic (DB) mice exposed to lethal doses of CCl4 (LD50,
1.25 ml/kg, ip), acetaminophen (LD80, 600 mg/kg, ip, APAP), and bromobenzene
(LD80, 0.5 ml/kg, ip) yielded 30, 20, and 20% mortality, respectively, indicating
hepatotoxic resistance. The objective was to investigate the mechanisms of
resistance against APAP-induced hepatotoxicity in DB mice. The hypothesis
that decreased bioactivation of APAP, altered toxicokinetics, and/or increased
tissue repair are the underlying mechanisms was investigated. Time course
studies after APAP (600 mg/kg, ip) treatment revealed identical initial liver
injury in non-DB and DB mice, which progressed only in the non-DB mice resulting
in 80% mortality. HPLC analysis revealed no difference in plasma t of APAP,
plasma & urinary APAP levels, and APAP detoxification via glucuronidation,
between the DB and non-DB mice. Hepatic CYP2E1 protein and activity, glutathione
and covalent binding of 14C-APAP did not differ between DB and non-DB mice,
suggesting that lower bioactivation-based liver injury was not the mechanism
of decreased hepatotoxicity in DB mice. Diabetes increased the number of S-phase
cells (8-fold) as assessed by PCNA assay in normally quiescent liver of these
mice. Inhibition of cell division by colchicine (CLC) intervention before
APAP treatment resulted in 70% mortality in the CLC intervened DB mice, indicating
that advancement of cells to S-phase is critical for protection against APAP
hepatotoxicity. Furthermore, in the DB mouse liver, over-expression of calpastatin,
an endogenous calpain inhibitor, in the newly dividing/divided cells explains
inhibition of the hydrolytic enzyme, calpain, in perinecrotic areas and lower
progression of APAP-initiated injury. These studies suggest that diabetes-associated
advancement of cells in the cell division cycle and higher compensatory tissue
repair protect type 2 DB mice from progression of APAP-initiated liver injury
that normally culminates in hepatic failure and mortality.
Citation: S.P.Sawant, A.V.Dnyanmote, M.S.Mitra,
J.Chilakapati, J.R.Latendresse, H.M.Mehendale. TYPE 2 DIABETIC MICE ARE PROTECTED
FROM ACETAMINOPHEN HEPATOTOXICITY. Abstract No. 1008. 2006 Itinerary Planner.
San Diego, CA: Society of Toxicology
Abstract Number: 459
DIETARY EFFECTS ON CELL PROLIFERATION AND APOPTOSIS IN P - NONYLPHENOL ( NP
) INDUCED POLYCYSTIC KIDNEY DISEASE ( PKD ) IN MALE SPRAGUE - DAWLEY RATS
S.M.Cooper1; X.Fu1; L.Muskhelishvili2;
J.R.Latendresse2; K.B.Delclos1. 1. National Center
for Toxicological Research, Jefferson, AR; 2. Toxicologic Pathology Associates,
Jefferson, AR.
Previous data show dietary NP (2000 ppm) from gestation day (GD)
7 induced PKD by postnatal day (PND) 50 in rats. Dietary modulation occurred
as rats fed soy-free diets (5K-96 and AIN-93G with casein (AIN-CAS)) had higher
relative kidney weight, larger cyst area, and higher incidence and severity
of PKD than rats fed soy containing diets (AIN-93G with soy protein isolate
(AIN-SPI) and Purina 5001(P5001)). As aberrant apoptosis and cell proliferation
have been associated with PKD, we investigated the potential role of the modulation
of these processes in diet-dependent NP-induced PKD. Weanling rats were raised
on one of the four diets and mated within diet groups. 2000 ppm NP was introduced
in the feed of half of the dams GD7 while half continued on control diets.
After parturition and weaning, pups continued the same treatment as their
dams until sacrifice on PND 14, 21, or 50. Cell proliferation was detected
by immunohistochemical staining for Ki-67 antigen and numbers of apoptotic
bodies (ApBs) were measured by TUNEL assay in renal sections. ApBs could not
be counted at PND 50 due to large necrotic areas in severely affected pups,
and there were no significant treatment effects on cell proliferation at PND
50. Neither diet nor NP affected cell proliferation in PND 14 pups. There
was a significant main effect (decrease) of NP on cell proliferation at PND
21, but no pairwise comparisons within diet groups were significant. In both
PND 14 and PND 21 pups, there was a main effect (increase) of NP on ApBs,
and pairwise comparisons indicated that NP induced significant increases in
ApBs relative to controls only in the soy-free diet groups. While there were
significant main effects of NP (decrease) on the ratio of cell proliferation
to ApBs at PND 14 and 21, there was no consistent difference among the diet
groups. The data suggest that induction of apoptosis by NP in renal tubules
of young male rats fed soy-free diets precedes the development of PKD.
Citation: S.M.Cooper, X.Fu, L.Muskhelishvili,
J.R.Latendresse, K.B.Delclos.
DIETARY EFFECTS ON CELL PROLIFERATION AND APOPTOSIS IN P - NONYLPHENOL
( NP ) INDUCED POLYCYSTIC KIDNEY DISEASE ( PKD ) IN MALE SPRAGUE - DAWLEY
RATS. Abstract No. 459. 2006 Itinerary Planner. San Diego, CA: Society
of Toxicology
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