Effect of polyunsaturated fatty acids on diphenyl hydantoin-induced genetic damage in vitro and in vivo

Ponnala, Shivani; Rao, K. Prabhakar; Chaudhury, Jaideep R.; Ahmed, Jaleel; Rao, Bonda Rama; Kanjilal, Sanjit; Hasan, Qurratulain; Das, Undurti N.

doi:10.1016/j.plefa.2008.11.008

Cited by 29 publications

(12 citation statements)

References 29 publications

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“…A 1 mL peripheral blood sample with 0.1 mL heparin was collected in a syringe. DNA was isolated from all these samples according to the standard procedure followed in the lab; and stored at -20°C until further use (Ponnala et al, 2009).…”

Section: Blood Collectionmentioning

confidence: 99%

Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Ponnala

Chaudhari

Jaleel

et al. 2012

Genetic Testing and Molecular Biomarkers

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Section: Blood Collectionmentioning

confidence: 99%

Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Ponnala

Chaudhari

Jaleel

et al. 2012

Genetic Testing and Molecular Biomarkers

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“…DNA was extracted from all the treated and untreated glioma cells as described earlier [15]. 1 μg of genomic DNA was loaded onto 0.8% agarose gel for analysis.…”

Section: Methodsmentioning

confidence: 99%

MMP-9 silencing regulates hTERT expression via β1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells

Ponnala

Chetty

Veeravalli

et al. 2011

Cellular Signalling

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In more than 90 percent of cancers including glioma, telomere elongation reverse transcriptase (hTERT) is overexpressed. In the present study, we sought to explore whether matrix metalloproteinase-9 (MMP-9) shRNA could alter hTERT-mediated proliferation in glioma cells. MMP-9 shRNA induced senescence and apoptosis in glioma cells by inhibiting hTERT expression and telomere activity. MMP-9 silencing decreased oncogenic c-Myc expression (hTERT activator), whereas the expression of the c-Myc antagonist MAD increased drastically (hTERT repressor); both c-Myc and MAD are transcription factors for hTERT. In addition, MMP-9 suppression turns the switch from c-Myc/MAX to MAD/MAX heterodimer binding to the hTERT promoter as determined by chromatin immunoprecipitation assay. We also show that silencing MAD via siRNA restored hTERT expression and inhibited senescence in glioma cells. MMP-9 transcriptional suppression decreased the expression of FAK, phosphor FAK and β1 integrin in glioma xenograft cells. Further, MMP-9 suppression decreased the interaction of β1 integrin/FAK and also MMP-9/β1 integrin as confirmed by immunoprecipitation analysis. Studies with either function blocking β1 integrin or FAK shRNA indicate that suppression of MMP-9 decreased β1 integrin-mediated induction of FAK, which led to decreased hTERT expression. Moreover, 4910 and 5310 glioma xenograft tissue sections from mice treated with MMP-9 shRNA showed reduced expression of FAK/c-Myc and elevated MAD levels. Decreased co-localization of β1 integrin and MMP-9 was associated with MMP-9-suppressed tumor sections. Further, immunoprecipitation analysis showed decreased association of proteins involved in telomere end repair in MMP-9 shRNA-treated glioma cells. Elevated levels of p73 and TRAIL and the results of the FACS analysis show induction of apoptosis in MMP-9-silenced glioma cells. Taken together, these data provide new insights into the mechanisms underlying MMP-9-mediated hTERT expression in glioma proliferation.

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“…In vitro effects of PHT 60 µg/ml alone; PHT + s9 and PHT + s9 combined with either TQ 1 µM or CMN 15 µM on glutathione (GSH) in isolated human lymphocytes after 72 h of incubation (one way ANOVA, mean ± SD). P = significant difference when compared with control normal group, P1 = significant difference when compared with PHT + S9 group, P2 = significant when compared with PHT 60 + S9 + CMN activation in Chinese hamster ovary cell (Winn et al, 2003), rodents (Kim et al, 1997), and some isolated human cells (Ponnala et al, 2009;Al-Jassabi and Azirun, 2010). This debate around the ability of PHT to induce 8-OH-dG (pg/106 cell) Figure 5.…”

Section: In Vitro Effects Of Phenytoin (Pht) and Pht + S9 On The Isolmentioning

confidence: 99%

“…Isolated lymphocytes from each blood samples were divided randomly into 5 groups, each of 6 samples: the 1 st group was none treated; the 2 nd treated with PHT 60 ug/ml (Ponnala et al, 2009); the 3 rd treated with PHT 60 ug/ml plus S9 (Sbrana et al, 1984, Ponnala et al, 2009; the 4 th treated with PHT 60 ug/ml (Ponnala et al, 2009) + S9 + TQ (Khader et al, 2009); the 5th treated with PHT 60 ug/ml + S9 + CMN (Siddique et al, 2010). The potential genotoxic drugs were added twice, at 24 and 48 h from the start of culture period and after stimulation of mitotic division with phytohaemagglutinin that was added at the start of culture period to induce mitosis within 24 h according to standard protocol of Poddar et al (2004).…”

Section: Plan Of the Study And Grouping Of Isolated Lymphocytesmentioning

confidence: 99%

Phenytoin: Is it genotoxic in isolated cultured human lymphocytes without metabolic activation by S9?

Naga¹,

Shata²,

kattawy³

2016

Afr. J. Pharm. Pharmacol.

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There are many conflicting reports around the phenytoin (PHT)-induced genotoxic effect especially in the in-vitro studies. PHT was claimed to cause genotoxic effect by the oxidative stress of its metabolic intermediates. However, by reviewing the distribution and activity of the enzymes responsible for PHT metabolism, we found that PHT is rarely metabolized by human lymphocytes. So that, we will use isolated cultured human lymphocytes to determine which is genotoxic, PHT itself or its metabolites? PHT 60 μg/ml were added to lymphocytes before and after metabolic activation by S9. Also, this study will investigate the possible antioxidant genoprotective effects of Thymoquinone (TQ) 1 μM and Curcumin (CMN) 15 μM on the chromosomal injury induced by PHT or its metabolites. After the end of culture period, the effects of PHT on the lymphocytes were investigated by measuring levels of chromosomal aberrations (CAs); mitotic index (MI); reduced glutathione (GSH); malondialdehyde (MDA); and 8-hydroxydeoxyguanosine (8-OH-dG). Only PHT after metabolic activation caused oxidative genotoxic effects which were significantly ameliorated by TQ more than CMN. Hence, the present study is the first to record that PHT without metabolic activation in isolated human lymphocytes from non epileptic donors cause dose dependant direct toxic effect rather than genotoxic effect.

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Effect of polyunsaturated fatty acids on diphenyl hydantoin-induced genetic damage in vitro and in vivo

Cited by 29 publications

References 29 publications

Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

Role of MDR1 C3435T and GABRG2 C588T Gene Polymorphisms in Seizure Occurrence and MDR1 Effect on Anti-Epileptic Drug (Phenytoin) Absorption

MMP-9 silencing regulates hTERT expression via β1 integrin-mediated FAK signaling and induces senescence in glioma xenograft cells

Phenytoin: Is it genotoxic in isolated cultured human lymphocytes without metabolic activation by S9?

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