Contributions of the pars lateralis, pars basilaris and femur to age estimations of the immature skeleton within a South African forensic setting:
- Thornton, Roxanne, Edkins, Adrienne L, Hutchinson, E F
- Authors: Thornton, Roxanne , Edkins, Adrienne L , Hutchinson, E F
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165451 , vital:41245 , https://0-doi.org.wam.seals.ac.za/10.1007/s00414-019-02143-9
- Description: Dental development and eruption sequences have prevailed as the gold standard in age estimations of previously unidentified immature individuals within a legal context. However, in the absence of the dentition, skeletal assessments have served as a frequently applied alternative. While various cranial and postcranial skeletal elements have been used in estimating age of the immature skeleton, little is known about the anthropometric value of the pars basilaris, pars lateralis and femur as skeletal age estimation tools. Thus, this study aimed to assess if these bones of the immature human skeleton were useful elements in estimating the age of prenatal and postnatal individuals. These bones were excised from the remains of 74 unclaimed human immature individuals and evaluated using traditional anthropometric methods. The study sample was sourced from the Johannesburg Forensic Pathology Services (JFPS) and the Johannesburg Forensic Paediatric Collection (JFPC), University of the Witwatersrand and subdivided into an early prenatal (younger than 30 gestational weeks); late prenatal (30 to 40 gestational weeks) and postnatal (birth to 7.5 months) age ranges.
- Full Text:
- Authors: Thornton, Roxanne , Edkins, Adrienne L , Hutchinson, E F
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165451 , vital:41245 , https://0-doi.org.wam.seals.ac.za/10.1007/s00414-019-02143-9
- Description: Dental development and eruption sequences have prevailed as the gold standard in age estimations of previously unidentified immature individuals within a legal context. However, in the absence of the dentition, skeletal assessments have served as a frequently applied alternative. While various cranial and postcranial skeletal elements have been used in estimating age of the immature skeleton, little is known about the anthropometric value of the pars basilaris, pars lateralis and femur as skeletal age estimation tools. Thus, this study aimed to assess if these bones of the immature human skeleton were useful elements in estimating the age of prenatal and postnatal individuals. These bones were excised from the remains of 74 unclaimed human immature individuals and evaluated using traditional anthropometric methods. The study sample was sourced from the Johannesburg Forensic Pathology Services (JFPS) and the Johannesburg Forensic Paediatric Collection (JFPC), University of the Witwatersrand and subdivided into an early prenatal (younger than 30 gestational weeks); late prenatal (30 to 40 gestational weeks) and postnatal (birth to 7.5 months) age ranges.
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Detection of the in vitro modulation of Plasmodium falciparum Arf1 by Sec7 and ArfGAP domains using a colorimetric plate-based assay:
- Swart, Tarryn, Khan, Farrah D, Ntlantsana, Apelele, Laming, Dustin, Veale, Clinton G L, Przyborski, Jude M, Edkins, Adrienne L, Hoppe, Heinrich C
- Authors: Swart, Tarryn , Khan, Farrah D , Ntlantsana, Apelele , Laming, Dustin , Veale, Clinton G L , Przyborski, Jude M , Edkins, Adrienne L , Hoppe, Heinrich C
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165418 , vital:41242 , https://0-doi.org.wam.seals.ac.za/10.1038/s41598-020-61101-3
- Description: The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated.
- Full Text:
- Authors: Swart, Tarryn , Khan, Farrah D , Ntlantsana, Apelele , Laming, Dustin , Veale, Clinton G L , Przyborski, Jude M , Edkins, Adrienne L , Hoppe, Heinrich C
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165418 , vital:41242 , https://0-doi.org.wam.seals.ac.za/10.1038/s41598-020-61101-3
- Description: The regulation of human Arf1 GTPase activity by ArfGEFs that stimulate GDP/GTP exchange and ArfGAPs that mediate GTP hydrolysis has attracted attention for the discovery of Arf1 inhibitors as potential anti-cancer agents. The malaria parasite Plasmodium falciparum encodes a Sec7 domain-containing protein - presumably an ArfGEF - and two putative ArfGAPs, as well as an Arf1 homologue (PfArf1) that is essential for blood-stage parasite viability. However, ArfGEF and ArfGAP-mediated activation/deactivation of PfArf1 has not been demonstrated.
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Hop depletion reduces HSF1 levels and activity and coincides with reduced stress resilience:
- Chakraborty, Abantika, Edkins, Adrienne L
- Authors: Chakraborty, Abantika , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165440 , vital:41244 , https://doi.org/10.1016/j.bbrc.2020.04.072
- Description: Heat-shock factor 1 (HSF1) regulates the transcriptional response to stress and controls expression of molecular chaperones required for cell survival. Here we report that HSF1 is regulated by the abundance of the Hsp70-Hsp90 organizing protein (Hop/STIP1).
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- Authors: Chakraborty, Abantika , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165440 , vital:41244 , https://doi.org/10.1016/j.bbrc.2020.04.072
- Description: Heat-shock factor 1 (HSF1) regulates the transcriptional response to stress and controls expression of molecular chaperones required for cell survival. Here we report that HSF1 is regulated by the abundance of the Hsp70-Hsp90 organizing protein (Hop/STIP1).
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HSP90 interacts with the fibronectin N-terminal domains and increases matrix formation:
- Chakraborty, Abir, Boel, Natasha M-E, Edkins, Adrienne L
- Authors: Chakraborty, Abir , Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165407 , vital:41241 , https://doi.org/10.3390/cells9020272
- Description: Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly.
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- Authors: Chakraborty, Abir , Boel, Natasha M-E , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165407 , vital:41241 , https://doi.org/10.3390/cells9020272
- Description: Heat shock protein 90 (HSP90) is an evolutionarily conserved chaperone protein that controls the function and stability of a wide range of cellular client proteins. Fibronectin (FN) is an extracellular client protein of HSP90, and exogenous HSP90 or inhibitors of HSP90 alter the morphology of the extracellular matrix. Here, we further characterized the HSP90 and FN interaction. FN bound to the M domain of HSP90 and interacted with both the open and closed HSP90 conformations; and the interaction was reduced in the presence of sodium molybdate. HSP90 interacted with the N-terminal regions of FN, which are known to be important for matrix assembly.
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Regulation of Kaposi’s Sarcoma-Associated Herpesvirus Biology by Host Molecular Chaperones:
- Kirigin, Elisa, Ruck, Duncan Kyle, Jackson, Zoe, Murphy, James, McDonnell, Euan, Okpara, Michael O, Whitehouse, Adrian, Edkins, Adrienne L
- Authors: Kirigin, Elisa , Ruck, Duncan Kyle , Jackson, Zoe , Murphy, James , McDonnell, Euan , Okpara, Michael O , Whitehouse, Adrian , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165385 , vital:41239 , ISBN , https://0-doi.org.wam.seals.ac.za/10.1007/7515_2020_18
- Description: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with development of the human diseases Kaposi’s sarcoma, Primary Effusion Lymphoma and Multicentric Castleman’s Disease. KSHV establishes a chronic latent infection in hosts, with periods of viral lytic replication, where both latent and lytic virus cycles contribute to malignancy, most often in the immunodeficient host.
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- Authors: Kirigin, Elisa , Ruck, Duncan Kyle , Jackson, Zoe , Murphy, James , McDonnell, Euan , Okpara, Michael O , Whitehouse, Adrian , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , book
- Identifier: http://hdl.handle.net/10962/165385 , vital:41239 , ISBN , https://0-doi.org.wam.seals.ac.za/10.1007/7515_2020_18
- Description: Kaposi’s sarcoma-associated herpesvirus (KSHV) is a gammaherpesvirus associated with development of the human diseases Kaposi’s sarcoma, Primary Effusion Lymphoma and Multicentric Castleman’s Disease. KSHV establishes a chronic latent infection in hosts, with periods of viral lytic replication, where both latent and lytic virus cycles contribute to malignancy, most often in the immunodeficient host.
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Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1, 3-benzoxazine derivatives
- Mbaba, Mziyanda, Dingle, Laura M K, Cash, Devon, de la Mare, Jo-Anne, Laming, Dustin, Taylor, Dale, Hoppe, Heinrich C, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
- Full Text:
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Cash, Devon , de la Mare, Jo-Anne , Laming, Dustin , Taylor, Dale , Hoppe, Heinrich C , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165395 , vital:41240 , https://doi.org/10.1016/j.ejmech.2019.111924
- Description: Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis.
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Ruthenium complexes with mono-or bis-heterocyclic chelates: DNA/BSA binding, Antioxidant and Anticancer studies
- Maikoo, Sanam, Chakraborty, Abir, Vukea, Nyeleti, Dingle, Laura M K, Samson, William J, de la Mare, Jo-Anne, Edkins, Adrienne L, Booysen, Irvin N
- Authors: Maikoo, Sanam , Chakraborty, Abir , Vukea, Nyeleti , Dingle, Laura M K , Samson, William J , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165463 , vital:41246 , DOI: 10.1080/07391102.2020.1775126
- Description: Deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) binding interactions for a series of ruthenium heterocyclic complexes were monitored using ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence emission spectroscopy and agarose gel electrophoresis. Investigations of the DNA interactions for the metal complexes revealed that they are groove-binders with intrinsic binding constants in the order of 104 – 107 M−1.
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- Authors: Maikoo, Sanam , Chakraborty, Abir , Vukea, Nyeleti , Dingle, Laura M K , Samson, William J , de la Mare, Jo-Anne , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165463 , vital:41246 , DOI: 10.1080/07391102.2020.1775126
- Description: Deoxyribonucleic acid (DNA) and bovine serum albumin (BSA) binding interactions for a series of ruthenium heterocyclic complexes were monitored using ultraviolet-visible (UV-Vis) spectrophotometry, fluorescence emission spectroscopy and agarose gel electrophoresis. Investigations of the DNA interactions for the metal complexes revealed that they are groove-binders with intrinsic binding constants in the order of 104 – 107 M−1.
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STIP1/HOP regulates the actin cytoskeleton through interactions with actin and changes in actin-binding proteins cofilin and profilin:
- Beckley, Samantha Joy, Hunter, Morgan C, Kituyi, Sarah N, Wingate, Ianthe, Chakraborty, Abantika, Schwarz, Kelly, Makhubu, Matodzi P, Rousseau, Robert P, Ruck, Duncan K, de la Mare, Jo-Anne, Blatch, Gregory L, Edkins, Adrienne L
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
- Full Text:
- Authors: Beckley, Samantha Joy , Hunter, Morgan C , Kituyi, Sarah N , Wingate, Ianthe , Chakraborty, Abantika , Schwarz, Kelly , Makhubu, Matodzi P , Rousseau, Robert P , Ruck, Duncan K , de la Mare, Jo-Anne , Blatch, Gregory L , Edkins, Adrienne L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165373 , vital:41238 , https://doi.org/10.3390/ijms21093152
- Description: Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
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Synthetic, characterization and cytotoxic studies of ruthenium complexes with Schiff bases encompassing biologically relevant moieties:
- Maikoo, Sanam, Dingle, Laura M K, Chakraborty, Abir, Xulu, Bheki, Edkins, Adrienne L, Booysen, Irvin N
- Authors: Maikoo, Sanam , Dingle, Laura M K , Chakraborty, Abir , Xulu, Bheki , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165429 , vital:41243 , https://doi.org/10.1016/j.poly.2020.114569
- Description: This research study describes the formation and characterization of novel paramagnetic ruthenium complexes, cis-Cl, trans-P-[RuIIICl2(carboim)(PPh3)2] with bidentate chelating carbohydrazide Schiff bases (carboim = bpc for 1, ttc for 2 and tpc for 3). These metal complexes were synthesized by the equimolar coordination reactions of trans-[RuCl2(PPh3)2] with N-[1,3-benzothiazole-2-ylmethylidene]pyridine-2-carbohydrazide (Hbpc), N-((uracil-5-yl)methylene)thiophene-2-carbohydrazide (Httc) and N-[(uracil-5-yl)methylidene]pyridine-2-carbohydrazide (Htpc), respectively. Physicochemical techniques including nuclear magnetic resonance-, electron-spin resonance- and infrared spectroscopy, UV–Vis spectrophotometry, voltammetry as well as molar conductivity measurements provided definitive determinations of the respective ruthenium compounds’ structures.
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- Authors: Maikoo, Sanam , Dingle, Laura M K , Chakraborty, Abir , Xulu, Bheki , Edkins, Adrienne L , Booysen, Irvin N
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/165429 , vital:41243 , https://doi.org/10.1016/j.poly.2020.114569
- Description: This research study describes the formation and characterization of novel paramagnetic ruthenium complexes, cis-Cl, trans-P-[RuIIICl2(carboim)(PPh3)2] with bidentate chelating carbohydrazide Schiff bases (carboim = bpc for 1, ttc for 2 and tpc for 3). These metal complexes were synthesized by the equimolar coordination reactions of trans-[RuCl2(PPh3)2] with N-[1,3-benzothiazole-2-ylmethylidene]pyridine-2-carbohydrazide (Hbpc), N-((uracil-5-yl)methylene)thiophene-2-carbohydrazide (Httc) and N-[(uracil-5-yl)methylidene]pyridine-2-carbohydrazide (Htpc), respectively. Physicochemical techniques including nuclear magnetic resonance-, electron-spin resonance- and infrared spectroscopy, UV–Vis spectrophotometry, voltammetry as well as molar conductivity measurements provided definitive determinations of the respective ruthenium compounds’ structures.
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The in vitro antiplasmodial and antiproliferative activity of new ferrocene-based α-aminocresols targeting hemozoin inhibition and DNA interaction:
- Mbaba, Mziyanda, Dingle, Laura M K, Swart, Tarryn, Cash, Devon, Laming, Dustin, de la Mare, Jo-Anne, Taylor, Dale, Hoppe, Heinrich C, Biot, Christophe, Edkins, Adrienne L, Khanye, Setshaba D
- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
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- Authors: Mbaba, Mziyanda , Dingle, Laura M K , Swart, Tarryn , Cash, Devon , Laming, Dustin , de la Mare, Jo-Anne , Taylor, Dale , Hoppe, Heinrich C , Biot, Christophe , Edkins, Adrienne L , Khanye, Setshaba D
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/149347 , vital:38827 , https://0-doi.org.wam.seals.ac.za/10.1002/cbic.202000132
- Description: Compounds incorporating ferrocene in a aminocresol scaffold showed antiplasmodial and anticancer activity. SAR studies revealed that an OH group and rotatable C–NH bond are vital for biological activity, with spectrophotometric techniques and docking simulations suggesting a dual mode of action involving hemozoin inhibition and DNA interaction. Targeting multiple pathways could delay the development of clinical resistance.
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Use of a non-hepatic cell line highlights limitations associated with cell-based assessment of metabolically induced toxicity:
- Weyers, Carli, Dingle, Laura M K, Wilhelmi, Brendan S, Edkins, Adrienne L, Veale, Clinton G L
- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
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- Authors: Weyers, Carli , Dingle, Laura M K , Wilhelmi, Brendan S , Edkins, Adrienne L , Veale, Clinton G L
- Date: 2020
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/160290 , vital:40431 , DOI: 10.1080/01480545.2019.1585869
- Description: Metabolically induced drug-toxicity is a major cause of drug failure late in drug optimization phases. Accordingly, in vitro metabolic profiling of compounds is being introduced at earlier stages of the drug discovery pipeline. An increasingly common method to obtain these profiles is through overexpression of key CYP450 metabolic enzymes in immortalized liver cells, to generate competent hepatocyte surrogates. Enhanced cytotoxicity is presumed to be due to toxic metabolite production via the overexpressed enzyme. However, metabolically induced toxicity is a complex multi-parameter phenomenon and the potential background contribution to metabolism arising from the use of liver cells which endogenously express CYP450 isoforms is consistently overlooked. In this study, we sought to reduce the potential background interference by applying this methodology in kidney-derived HEK293 cells which lack endogenous CYP450 expression.
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