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In Vitro Approaches to Assess Mitochondrial Toxicity And In Vitro Approaches to Assess Mitochondria-Mediated Drug Toxicity: Advantages and Limitations and a Decade of Learning's Yvonne Will, Ph.D Pfizer Research & Development Groton, CT [email protected] 48 Drugs Were Withdrawn for Safety Reasons Between 1990-2007 Cerivastatin Troglitazone Tolcapone Nefazodone 18 Hepatotoxic 21 Cardiotoxic 9 Others Mitochondrial Impairment of Drugs Receiving Black Box Warnings Hepatotoxicity Cardiovascular Antivirals Antibiotics Anthracyclines Anti-Cancer Abacavir Isoniazid Daunorubicin Arsenic Trioxide Didanosine Ketoconazole (oral) Doxorubicin Cetuximab Emtricitabine Streptozocin Epirubicin Denileukin diftitox Entecavir Trovafloxacin Idarubicin Mitoxantrone Emtricitabine Tamoxifen Lamivudine CNS NSAIDs Nevirapine Dantrolene Celecoxib Beta-Blocker] Telbivudine Divalproex Sodium Diclofenac Atenolol Tenofovir Felbamate Diflunisal Tipranavir Naltrexone Etodolac Antiarhythmic Stavudine Nefazodone Fenoprofen Amiodarone (oral) Zalcitabine Valproic Acid/ Ibuprofen Disopyramide Zidovudine Indomethacin Dofetilide Hypertension Ketoprofen Ibutilide Anti-Cancer Bosentan Mefenamic acid Flutamide Meloxicam CNS Dacarbazine Naproxen Amphetamines Gemtuzumab Nabumetone Atomoxetin Methotrexate Oxaprozin Droperidol Pentostatin Piroxicam Methamphetamine Tamoxifen Salsalate Pergolide Sulindac Thioridazine Diabetes Tolmetin Pioglitazone Rosiglitazone Anaesthetic Bupivacaine Early mitochondrial assessment allows the identification of compounds with the desired efficacy profile, but without ancillary liabilities. Many Different Mechanisms Lead to Mitochondrial Dysfunction Dykens et al. (2007) Expert Rev. Mol. Diagn. 7,161-175, with permission Objectives/Outline: • Drug withdrawn from the market exhibit mitochondrial liabilities • Assays to detect mitochondrial toxicity • Assay for measuring Oxygen consumption of isolated mitochondria. • Cell viability assay in (a) Glucose medium, (b) Galactose medium. • Assay for measuring Oxygen consumption and extracellular acidification of cells. • Assays for measuring changes in mtDNA and mtDNA-encoded protein levels in cells. • Summary Polarographic Mitochondrial Respiration Drug Mitos Substrate ADP Basal Respiration Inhibition Maximum Respiration O2 ADP-Driven All ADP phosphorylated Uncoupling Time (min) 20min Oxygen consumption Measurement in Isolated Mitochondria • Phosphorescent • Water-soluble 1 5 Deoxygenated • Cell non-invasive 0.8 4 • Non-cytotoxic 0.6 3 • Stable Intensity 0.4 2 • Time resolved or prompt Fold Increase Air-saturated 0.2 1 • Compatible with any reader Normalised • Large stoke shift allows for 0 0 300 400 500 600 600 620 640 660 680 700 high signal to noise ratio Wavelength (nm) Wavelength (nm) • multiplex with “green dyes” Assay Set-Up 96 Well Plate Mitochondria with Probe substrate +/- ADP Mineral Oil PC Plate reader Output of Fluorescent Data from the Oxygen-Sensing Probe with Isolated Mitochondria Basal respiration Uncoupler Inhibitor Vehicle Dykens et al. (2007) Expert Rev. Mol. Diagn. 7,161-175, with permission Mitochondrial Effects of Thiozolidinediones Vary State 2 BasalState respiration 2 Ciglitazone Ciglitazone Troglitazone 10000 Troglitazone 10000 Darglitazone Withdrawn Darglitazone ) 8000 Rosiglitazone ) 8000 Rosiglitazone SE + SE 6000 Pioglitazone + 6000 MuraglitazarPioglitazone RFU Muraglitazar Blackbox warning RFU 4000 (mean 4000 (mean Control 2000 Control 2000 0 0 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Time (min) Time (min) State 3 ADPState-Driven 3 15000 15000 Control Control 12000 12000 ) ) SE 9000 + SE 9000 Pioglitazone + Pioglitazone Blackbox warning Rosiglitazone RFU 6000 Rosiglitazone RFU 6000 Muraglitazar (mean Muraglitazar (mean 3000 Ciglitazone 3000 DarglitazoneCiglitazone Darglitazone Withdrawn 0 Troglitazone 0 Troglitazone 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 Time (min) Time (min) Nadanaciva et al. (2007) Toxicol. Appl. Drugs present at 25nmol/mg mitochondrial protein. N=4, except for controls N=48. Drugs present at 25nmol/mg mitochondrial protein. N=4, except for controls N=48. Pharmacol. 223, 277-287, with permission Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 2008 Dec 1;233(2):203-10. Bioaccumulation Will Y, Dykens JA, Nadanaciva S, Hirakawa B, Jamieson J, Marroquin LD, Hynes J, Patyna S, Jessen BA. Effect of the multi-targeted tyrosine kinase inhibitors imatinib, dasatinib, sunitinib, and sorafenib on mitochondrial function in isolated rat heart mitochondria and H9c2 cells. Toxicol Sci. 2008 Nov;106(1):153-61. Liver toxicity of sorafenib Dykens JA, Jamieson JD, Marroquin LD, Nadanaciva S, Xu JJ, Dunn MC, Smith AR, Will Y. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci. 2008 Jun;103(2):335-45. rank order correct, need additional risk factors Nadanaciva S, Dykens JA, Bernal A, Capaldi RA, Will Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol Appl Pharmacol. 2007 Sep 15;223(3):277-87. rank order correct, Cmax , accumulation Summary: Oxygen Consumption of Isolated Mitochondria • Values: • Identifies inhibitors and uncouplers of the electron transport chain • High-throughput; highly reproducible; easy to use • May be used to identify structure-activity-relationships • Learnings: Can rank order compounds within a series for their mitochondrial toxicity effects. Rankorder in most cases correlates with toxicity profile in the clinic. Cmax information strengthen readout ( exceptions like statins and biguanides) • Limitations: • Can potentially overestimate toxicity since the isolated organelle is being used • Identifies only immediate (acute) effects; may need to pre-incubate mitochondria with drug • Does not take into account conversion of parent drug reactive/inactive metabolites Aerobically Poised Cell Models oxygen & pH sensors Objectives/Outline: • Drug withdrawn from the market exhibit mitochondrial liabilities • Assays to detect mitochondrial toxicity • Assay for measuring Oxygen consumption of isolated mitochondria. • Cell viability assay in (a) Glucose medium, (b) Galactose medium. • Assay for measuring Oxygen consumption and extracellular acidification of cells. • Assays for measuring changes in mtDNA and mtDNA-encoded protein levels in cells. • Summary Circumventing the Crabtree Effect: The “Glucose- Galactose” Model Crabtree Effect (1929): inhibition of respiration by elevated glucose. Warburg Effect (1929): aerobic glycolysis yields lactate despite competent mitochondria. Contemporary cell culture often uses 25mM glucose media (5X physiological!) Transformed cells are often characterized by low rates of O2 consumption & resistance to mitotoxicants. Marroquin et al. (2007) Toxicol. Sci., 97, 539-547 Cells Grown in Galactose Become Susceptible to Mitochondrial Toxicants 120 120 100 100 80 * 80 * * 60 60 ATP ATP 40 40 (% Control) (% (% Control) (% % ATP Control % ATP 20 20 0 0 0.001 0.01 0.1 1 0.0001 0.001 0.01 0.1 1 10 [Rotenone] M [Antimycin] M 120 120 100 100 * * 80 80 60 60 ATP 40 ATP 40 * (% Control) (% 20 Control) (% 20 0 0 0.0001 0.001 0.01 0.1 1 10 0.01 0.1 1 10 100 1000 [Oligomycin] M [FCCP] M Marroquin LD, Hynes J, Dykens JA, Jamieson JD, Will Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol Sci. 2007 Jun;97(2):539-47. Cells Grown in Galactose are More Susceptible to Mitochondrial Toxicants such as Nefazodone 120 100 80 50 45 38.4 40 35 60 30 25 20 IC50 (µM) 15 % ATP Control 8.98 40 10 5 0 Galactose Glucose 20 Cell Culture Media 0 0.01 0.1 1 10 100 Concentration (µM) Dykens et al. (2008) Toxicol. Sci., 103, 335-345 Correlating The RST and HepG2 Glu-Gal Assays A compound could belong to any of the following categories: RST assay HepG2 Glucose-Galactose assay Mechanism of Toxicity More toxic in Gal than Glu Toxicity primarily through mitochondrial effects (<5% of compounds) Not toxic in either medium Compound may be converted to inactive metabolite or does not get into cells Equally toxic in both media Multiple mechanisms of toxicity (most of RST positives) - More toxic in Gal than Glu Compound may affect apoptosis, impair fatty acid transport, activate HIF-1a - More toxic in Glu than Gal Compound may impair glycolysis - Equally toxic in both media Toxicity primarily through non-mitochondrial “off-targets” Objectives/Outline: • Drug withdrawn from the market exhibit mitochondrial liabilities • Assays to detect mitochondrial toxicity • Assay for measuring Oxygen consumption of isolated mitochondria. • Cell viability assay in (a) Glucose medium, (b) Galactose medium. • Assay for measuring Oxygen consumption and extracellular acidification of cells. • Assays for measuring changes in mtDNA and mtDNA-encoded protein levels in cells. • Summary The O2 Consumption Rate of Cells is a Measure of Mitochondrial Respiration Glucose O2 G6P O2 + NAD H2O Acetyl-CoA ATP Glycolysis NADH ATP ADP ADP Pyruvate Lactic Acid Extracellular Acidification Rate of Cells is a Measure of Glycolysis Phenformin and Buformin Decrease Oxygen Consumption in HepG2 cells Oxygen Consumption Rate 125M 125M 125M 125M DMSO Metformin Buformin Phenformin % change % in oxygen consumption HepG2 cells Dykens et al. (2008) Toxicol. Appl. Pharmacol. 233,
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