etters

Abstracts / Toxicology L

observed as well as an increased intake of water in both sexes.(4) To predict gliclazide absorption in vivo, the permeability ofgliclazide across Caco-2 monolayer was studied. The transportamount of gliclazide was determined by HPLC to calculate theapparent permeability coefficient (Papp). The Papp of gliclazide wasabout 25 × 10−6 cm/s for doses 10, 100 and 300 �M at pH 7.4 andincreased 3 times when pH gradient was used. The Papp value ofgliclazide ranks gliclazide among drugs with high absorbed fractionin humans.

doi:10.1016/j.toxlet.2008.06.639

T46Mechanistic understanding of in silico toxicity predictions

Diana Suarez ∗, Carol A. Marchant, Mukesh L. Patel

Lhasa Limited, Leeds, North Yorkshire, United Kingdom

The use of structural alerts in the in silico prediction of toxicityhas been advocated in the context of regulatory legislation such asREACH. Implementation of such alerts in an expert system allowstheir reproducible application and the provision of supporting evi-dence to explain their basis. This evidence can include informationon the mechanism of toxicity which may be important, for example,in understanding the significance of the contribution of a particularstructural feature to a toxicity prediction.

One structural feature type found in a diverse range of chemicalstructures is the aromatic ring. Aromatic rings possess a variety ofproperties which allow them to contribute to toxicity in a number ofdifferent ways. These include their ability to (i) undergo metabolicactivation to reactive species, (ii) stabilise charged or radical inter-mediates and/or (iii) form hydrophobic interactions or otherwisecontribute to a chemical’s lipophilicity.

The work presented here describes the development ofstructural alerts for the in silico prediction of hepatotoxicitywhich illustrate these different roles through discussion of theadverse hepatic effects associated with exposure to halobenzenes,pyrrolizidine alkaloids and tetracyclines.

doi:10.1016/j.toxlet.2008.06.640

T47Catechin abrogates tamoxifen-induced liver mitochondrial tox-icity

Heena Tabassum 1,∗, Suhel Parvez 2, Detlef Siemen 2, BasudevBanerjee 1, Sheikh Raisuddin 3

1 UCMS & GTB Hospital, University of Delhi, Delhi, India, 2 Universityof Magdeburg, Magdeburg, Germany, 3 Hamdard University, NewDelhi, India

Tamoxifen (TAM) is a selective estrogen receptor modulator used inthe treatment of breast cancer and is currently the world’s largestselling drug for that purpose. It brings about a collapse of the mito-chondrial membrane potential by acting both as an uncouplingagent and a powerful inhibitor of mitochondrial electron transportchain. Using specific nutrients to protect tissue against toxic andcarcinogenic injury is one of the most attractive approaches in dis-ease prevention. The present study was undertaken to investigatemodulatory effects of catechin, an antioxidant flavonoid present ingreen and black tea on the toxicity of TAM, with special referenceto protection against disruption of drug metabolizing and antioxi-dant enzymes in Swiss albino mice. TAM caused a significant rise inthe mitochondrial lipid peroxidation (LPO), protein carbonyls (PC)and superoxide radical production. Pretreatment of mice with cat-

180S (2008) S32–S246 S59

echin (40 mg kg) marked attenuation of increased mitochondrialLPO, PC content and superoxide production. The present findingdemonstrates that the antioxidative potential of catechin could beattributed to its modulatory effect on xenobiotic bioactivation anddetoxification processes.

doi:10.1016/j.toxlet.2008.06.641

T48Experimental approaches in toxicity minimization forantileukemic drugs regime

Susanna Tanina ∗, Tatyana Karatsuba

SI Institute of Pharmacology and Toxicology, Kiev, Ukraine

Before main experiments were estimated toxicity and antineoplas-tic activity (rats with lymphosarcoma) of ingredients for originatingcombination. Phtorafurum in dose 183.0 mg/kg by 6 administra-tion in 12 days (48 ours interval) gave tumor growth inhibitionabout 90%, adriablastin in dose 0.35 mg/kg by 2 administration gaveabout 51.0% of tumor growth inhibition (corresponds to significancecriterion). Minimization of mentioned ingredients up to 90.0, 1.4and 0.14 mg/kg correspondently in combination on this model gave81.0% of inhibition. Execution of established combination was pro-vided on lymphoid leukemia L1210—model of leucosis. As a donorswere used mouse (DBA/2 line) with ascites. Donors ascites wasplaned in sterile conditions in physiological solution up to concen-tration 1× 10 crates in 1 ml by 0.1 ml to mice of DBA/2 line. As aresult we got about 56.0% of increasing of life expectancy (the sig-nificance criterion, 25.0%). Thus, use of this experimental modelof leucosis allows estimate possible toxic influence of agents onanimal’s life expectancy.

doi:10.1016/j.toxlet.2008.06.642

T49Evaluation of molecular markers of renal toxicity caused byproximal tubule segment-specific nephrotoxicants in a time-course study

Arianna Chiusolo 1,2,∗, Rossella Defazio 1,2, AlessandroCasartelli 1,2, N. Mori 1,2, Patrizia Cristofori 1,2, MicheleMongillo 1,2, Edoardo Zanetti 1,2, Andrea Trevisan 1,2

1 GlaxoSmithKline, Verona, Italy, 2 University of Padova, Padova, Italy

As a consequence of the difficulties in assessing early renal damageby currently available/traditional biomarkers, there is an ongo-ing interest in developing new biomarkers of nephrotoxicity. Anemerging approach to achieve this objective is the use of genomictechnologies.

The aim of the present study was to monitor by qRT-PCR mRNAlevels of some genes specifically expressed in the injured and/orregenerating kidney cells after treatment with segment-specificnephrotoxicants and correlate their changes with histopathologicalfindings and clinical markers (creatinine, urea, glutamine syn-thetase (GS)) of renal damage.

Male Wistar rats 8 weeks old were treated (n = 4) with sin-gle administration of 100 mg/kg b.w. hexachloro-1:3-butadiene(HCBD), or 25 mg/kg b.w. of potassium dichromate (Cr). Kidneyand blood samples were collected after 6, 12, 24, 48, 72, and 96 hafter treatment. The following genes were evaluated: kidney injurymolecule-1 (KIM-1), clusterin (Cln), regucalcin (Rgn), and osteo-pontin (Spp1) according to their involvement in tissue damage,remodelling and regeneration, disruption of calcium homeostasis,oxidative stress.