Rapid toxicity testing based on mitochondrial respiratory activity

Haubenstricker, M. E.; Holodnick, S. E.; Mancy, K. H.; Brabec, Michael J.

doi:10.1007/bf01701787

Cited by 14 publications

(6 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The lower Ca 2+ threshold for triggering mPTP opening in bupivacaine group was not due to the lower quality of the mitochondrial preparation in this group, as the respiratory control ratio in both Bup and LE groups was greater than 4 (Fig. 3A–C)(35;36). Our results highlight the role of mPTP in reversal of cardiotoxicity by LE.…”

Section: Discussionmentioning

confidence: 82%

Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats*

Partownavid

Umar

et al. 2012

Critical Care Medicine

View full text Add to dashboard Cite

OBJECTIVES Lipid Emulsion (LE) has been shown to be effective in resuscitating bupivacaine-induced cardiac arrest but its mechanism of action is not clear. Here we investigated whether fatty acid oxidation is required for rescue of bupivacaine induced cardiotoxicity by LE in rats. We also compared the mitochondrial function and calcium threshold for triggering of mitochondrial permeability transition pore (mPTP) opening in bupivacaine-induced cardiac arrest before and after resuscitation with LE. DESIGN Prospective, randomized, animal study. SETTING University Research Laboratory. SUBJECTS Adult male Sprague-Dawley rats. INTERVENTIONS Asystole was achieved with a single dose of bupivacaine (10mg/kg over 20seconds, i.v.) and 20% LE infusion (5ml/kg bolus, and 0.5ml/kg/min maintenance) with cardiac massage started immediately. The rats in CVT group were pretreated with a single dose of fatty acid oxidation inhibitor CVT (0.5, 0.25, 0.125 or 0.0625mg/kg bolus i.v.) 5min prior to inducing asystole by bupivacaine overdose. Heart rate (HR), ejection fraction (EF), fractional shortening (FS), the threshold for opening of mPTP, oxygen consumption and membrane potential were measured. The values are Mean±SEM. MEASUREMENTS AND MAIN RESULTS Administration of bupivacaine resulted in asystole. ILP infusion improved the cardiac function gradually as the EF was fully recovered within 5min (EF=64±4% and FS=36±3%, n=6) and heart rate increased to 239±9 beats/min (71% recovery, n=6) within 10min. LE was only able to rescue rats pretreated with low dose of CVT (0.0625mg/kg) (HR=~181±11 beats/min at 10 min, recovery of 56%; EF=50±1%; FS=26±0.6% at 5min, n=3) but was unable to resuscitate rats pretreated with higher doses of CVT (0.5, 0.25 or 0.125mg/kg). The calcium retention capacity in response to Ca2+ overload was significantly higher in cardiac mitochondria isolated from rats resuscitated with 20% LE compared to the group that did not receive ILP after bupivacaine-overdose (330±42 vs. 180±8.2 nmol/mg-mitochondrial protein, p<0.05, n=3 in each group). The mitochondrial oxidative rate and membrane potential were similar in bupivacaine group before and after resuscitation with LE infusion. CONCLUSIONS Fatty acid oxidation is required for successful rescue of bupivacaine induced cardiotoxicity by LE. This rescue action is associated with inhibition of mitochondrial permeability transition pore opening.

show abstract

Section: Discussionmentioning

confidence: 82%

Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats*

Partownavid

Umar

et al. 2012

Critical Care Medicine

View full text Add to dashboard Cite

show abstract

“…Any interference with mitochondrial bioenergetics is known to be a part of cell injury process by a multiplicity of mechanisms and assorted agents (Wallace, 2008;Wallace, Eells, Madeira, Cortopassi, & Jones, 1997). Mitochondria has proven to be an excellent model to evaluate the many xenobiotics' effects on cell toxicity and the obtained data are usually in good agreement with cytotoxicity parameters reported in cell cultures and whole organisms (Haubenstricker, Holodnick, Mancy, & Brabec, 1990;Knobeloch, Blondin, Read, & Harkin, 1990). Based on these facts, the purpose of the present study was the assessment of potential toxicological effects of P. tridentatum flowers water extracts.…”

Section: Introductionmentioning

confidence: 85%

Antioxidant capacity and toxicological evaluation ofPterospartum tridentatumflower extracts

Ferreira

Dinis

Azedo

et al. 2012

CyTA - Journal of Food

View full text Add to dashboard Cite

Pterospartum tridentatum Willk. (prickled broom) is an autochthonous plant, common in Portuguese territory. The yellow flowers are used in traditional medicine, as a potential cure for all body illnesses, mainly to treat throat irritations or for diabetes, hypertension and hypercholesterolemia therapy. Despite its traditional use, no toxicological assessment has been performed to our knowledge. A high antioxidant activity of P. tridentatum flower water extract was found, in good agreement with its electrospray ionisation-mass spectroscopy (ESI-MS) spectrum which revealed the presence of several flavonoids, such as luteolin-O-(O-acetyl)-glucuronide, luteolin-Oglucuronide or isorhamnetin-O-hexoside. Mitocondrial respiratory rates (state 4, state 3 and FCCP-stimulated respiration) and respiratory indexes (respiratory control and P/O ratios) showed no consistent decrease of respiratory and phosphorylative efficiencies for the concentrations tested (up to 500 mg.mL 71 ). Cytotoxicity evaluation, using MTT assay, was in agreement with the previous results. In conclusion, for the concentration range commonly used, P. tridentatum flower usage can be regarded as harmless and credible.Keywords: antioxidant capacity; cytotoxicity; oxidative phosphorylation; phytotherapy; Pterospartum tridentatum (L.); Willk.; toxicologic evaluation Pterospartum tridentatum Willk. es una planta auto´ctona comu´n en el territorio portugue´s. Las flores amarillas se usan en medicina tradicional como cura potencial para todas las enfermedades, especialmente para tratamientos de irritacio´n de garganta o para tratamientos contra diabetes, hipertensio´n o hipercolesterolemia. A pesar de su uso tradicional, ninguna evaluacio´n toxicolo´gica se ha llevado a cabo. Se encontro´una alta actividad antioxidante de extracto acuoso de flor de P. Tridentatum, concordando con su espectro ESI-MS, el cual revelo´la presencia de varios flavonoides, como luteolina O-(O-acetil)-glucuro´nido, luteolina-Oglucuro´nido o isorramntina-O-hexo´sido. Las frecuencias respiratorias mitocondriales (estado 4, estado 3 y respiracio´n estimulada por FCCP) mostraron un descenso no consistente de eficiencia respiratoria y fosforilativa para las concentraciones analizadas (hasta 500 mg.mL -1 ). La evaluacio´n de citotoxicidad, usando ensayo MTT, coincidio´con los resultados previos. En conclusio´n, para las concentraciones comu´nmente empleadas, el uso de las flores de P. tridentatum se puede considerar inocuo y verosı´mil.Palabras claves: capacidad antioxidante; citotoxicidad; fosforilacio´n oxidativa; fitoterapia; Pterospartum tridentatum (L.) Willk; evaluacio´n toxicolo´gica Abbreviations: ESI, electrospray ionization; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HepG2, a human hepatoma cell line; MS, mass spectrometry; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; P/O ratio, ratio of ADP molecules phosphorylated to atoms of oxygen consumed; RCR, respiratory control ratio (state 3 respiratory rate/state 4 respiratory rate)

show abstract

“…Metabolism, respiration, and aerobic scope (the difference between maximal and resting rates of O 2 consumption) are linked to growth, reproduction, activity, functional performance, and many important behaviors. − Exposure to aquatic pollution may require that energy be redirected toward detoxification and cellular protection, particularly in tissues that accumulate contaminants and/or play large roles in detoxification (e.g., liver), and may thus impact whole-animal metabolism. Exposure may constrain these processes, because some contaminants cause mitochondrial dysfunction and impair energy production. − Although some studies have investigated the effects of pollution on energy stores (i.e., concentrations of lipid, glycogen, and protein in tissues; − ), the mechanisms and functional implications on higher levels of biological organization (i.e., organ systems and whole-organism) remain unclear. This knowledge gap is best-addressed using integrative sets of bioenergetic markers that provide a mechanistic link between cellular changes and organismal metabolism.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Costs of Exposure to Wastewater Effluent Lead to Compensatory Adjustments in Respiratory Physiology in Bluegill Sunfish

McCallum

Vaseghi‐Shanjani

et al. 2018

Environ. Sci. Technol.

View full text Add to dashboard Cite

Municipal wastewater effluent is a major source of aquatic pollution and has potential to impact cellular energy metabolism. However, it is poorly understood whether wastewater exposure impacts whole-animal metabolism and whether this can be accommodated with adjustments in respiratory physiology. We caged bluegill sunfish (Lepomis macrochirus) for 21 days at two sites downstream (either 50 or 830 m) from a wastewater treatment plant (WWTP). Survival was reduced in fish caged at both downstream sites compared to an uncontaminated reference site. Standard rates of O consumption increased in fish at contaminated sites, reflecting a metabolic cost of wastewater exposure. Several physiological adjustments accompanied this metabolic cost, including an expansion of the gill surface area available for gas exchange (reduced interlamellar cell mass), a decreased blood-O affinity (which likely facilitates O unloading at respiring tissues), increased respiratory capacities for oxidative phosphorylation in isolated liver mitochondria (supported by increased succinate dehydrogenase, but not citrate synthase, activity), and decreased mitochondrial emission of reactive oxygen species (ROS). We conclude that exposure to wastewater effluent invokes a metabolic cost that leads to compensatory respiratory improvements in O uptake, delivery, and utilization.

show abstract

Rapid toxicity testing based on mitochondrial respiratory activity

Cited by 14 publications

References 13 publications

Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats*

Fatty-acid oxidation and calcium homeostasis are involved in the rescue of bupivacaine-induced cardiotoxicity by lipid emulsion in rats*

Antioxidant capacity and toxicological evaluation ofPterospartum tridentatumflower extracts

Metabolic Costs of Exposure to Wastewater Effluent Lead to Compensatory Adjustments in Respiratory Physiology in Bluegill Sunfish

Contact Info

Product

Resources

About