AutomaticOptimizationofan Silico ModelofHumaniPSCDerived ...
Mechanistic understanding of in silico toxicity predictions
1
Abstracts / Toxicology Letters 180S (2008) S32–S246 S59 observed as well as an increased intake of water in both sexes. (4) To predict gliclazide absorption in vivo, the permeability of gliclazide across Caco-2 monolayer was studied. The transport amount of gliclazide was determined by HPLC to calculate the apparent permeability coefficient (Papp). The Papp of gliclazide was about 25 × 10 −6 cm/s for doses 10, 100 and 300 M at pH 7.4 and increased 3 times when pH gradient was used. The Papp value of gliclazide ranks gliclazide among drugs with high absorbed fraction in humans. doi:10.1016/j.toxlet.2008.06.639 T46 Mechanistic 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 toxicity has been advocated in the context of regulatory legislation such as REACH. Implementation of such alerts in an expert system allows their reproducible application and the provision of supporting evi- dence to explain their basis. This evidence can include information on the mechanism of toxicity which may be important, for example, in understanding the significance of the contribution of a particular structural feature to a toxicity prediction. One structural feature type found in a diverse range of chemical structures is the aromatic ring. Aromatic rings possess a variety of properties which allow them to contribute to toxicity in a number of different ways. These include their ability to (i) undergo metabolic activation to reactive species, (ii) stabilise charged or radical inter- mediates and/or (iii) form hydrophobic interactions or otherwise contribute to a chemical’s lipophilicity. The work presented here describes the development of structural alerts for the in silico prediction of hepatotoxicity which illustrate these different roles through discussion of the adverse hepatic effects associated with exposure to halobenzenes, pyrrolizidine alkaloids and tetracyclines. doi:10.1016/j.toxlet.2008.06.640 T47 Catechin abrogates tamoxifen-induced liver mitochondrial tox- icity Heena Tabassum 1,∗ , Suhel Parvez 2 , Detlef Siemen 2 , Basudev Banerjee 1 , Sheikh Raisuddin 3 1 UCMS & GTB Hospital, University of Delhi, Delhi, India, 2 University of Magdeburg, Magdeburg, Germany, 3 Hamdard University, New Delhi, India Tamoxifen (TAM) is a selective estrogen receptor modulator used in the treatment of breast cancer and is currently the world’s largest selling drug for that purpose. It brings about a collapse of the mito- chondrial membrane potential by acting both as an uncoupling agent and a powerful inhibitor of mitochondrial electron transport chain. Using specific nutrients to protect tissue against toxic and carcinogenic injury is one of the most attractive approaches in dis- ease prevention. The present study was undertaken to investigate modulatory effects of catechin, an antioxidant flavonoid present in green and black tea on the toxicity of TAM, with special reference to protection against disruption of drug metabolizing and antioxi- dant enzymes in Swiss albino mice. TAM caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyls (PC) and superoxide radical production. Pretreatment of mice with cat- echin (40 mg kg) marked attenuation of increased mitochondrial LPO, PC content and superoxide production. The present finding demonstrates that the antioxidative potential of catechin could be attributed to its modulatory effect on xenobiotic bioactivation and detoxification processes. doi:10.1016/j.toxlet.2008.06.641 T48 Experimental approaches in toxicity minimization for antileukemic 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 originating combination. Phtorafurum in dose 183.0mg/kg by 6 administra- tion in 12 days (48 ours interval) gave tumor growth inhibition about 90%, adriablastin in dose 0.35 mg/kg by 2 administration gave about 51.0% of tumor growth inhibition (corresponds to significance criterion). Minimization of mentioned ingredients up to 90.0, 1.4 and 0.14 mg/kg correspondently in combination on this model gave 81.0% of inhibition. Execution of established combination was pro- vided on lymphoid leukemia L1210—model of leucosis. As a donors were used mouse (DBA/2 line) with ascites. Donors ascites was planed in sterile conditions in physiological solution up to concen- tration 1× 10 crates in 1ml by 0.1ml to mice of DBA/2 line. As a result we got about 56.0% of increasing of life expectancy (the sig- nificance criterion, 25.0%). Thus, use of this experimental model of leucosis allows estimate possible toxic influence of agents on animal’s life expectancy. doi:10.1016/j.toxlet.2008.06.642 T49 Evaluation of molecular markers of renal toxicity caused by proximal tubule segment-specific nephrotoxicants in a time- course study Arianna Chiusolo 1,2,∗ , Rossella Defazio 1,2 , Alessandro Casartelli 1,2 , N. Mori 1,2 , Patrizia Cristofori 1,2 , Michele Mongillo 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 damage by currently available/traditional biomarkers, there is an ongo- ing interest in developing new biomarkers of nephrotoxicity. An emerging approach to achieve this objective is the use of genomic technologies. The aim of the present study was to monitor by qRT-PCR mRNA levels of some genes specifically expressed in the injured and/or regenerating kidney cells after treatment with segment-specific nephrotoxicants and correlate their changes with histopathological findings 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 100mg/kg b.w. hexachloro-1:3-butadiene (HCBD), or 25mg/kg b.w. of potassium dichromate (Cr). Kidney and blood samples were collected after 6, 12, 24, 48, 72, and 96h after treatment. The following genes were evaluated: kidney injury molecule-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.
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Transcript of Mechanistic understanding of in silico toxicity predictions
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Abstracts / Toxicology Lobserved 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.
