Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro
Abstract
As a class, the biguanides induce lactic acidosis, a hallmark of mitochondrial impairment. To assess potential mitochondrial impairment, we evaluated the effects of metformin, buformin and phenformin on: 1) viability of HepG2 cells grown in galactose, 2) respiration by isolated mitochondria, 3) metabolic poise of HepG2 and primary human hepatocytes, 4) activities of immunocaptured respiratory complexes, and 5) mitochondrial membrane potential and redox status in primary human hepatocytes. Phenformin was the most cytotoxic of the three with buformin showing moderate toxicity, and metformin toxicity only at mM concentrations. Importantly, HepG2 cells grown in galactose are markedly more susceptible to biguanide toxicity compared to cells grown in glucose, indicating mitochondrial toxicity as a primary mode of action. The same rank order of potency was observed for isolated mitochondrial respiration where preincubation (40 min) exacerbated respiratory impairment, and was required to reveal inhibition by metformin, suggesting intramitochondrial bio-accumulation. Metabolic profiling of intact cells corroborated respiratory inhibition, but also revealed compensatory increases in lactate production from accelerated glycolysis. High (mM) concentrations of the drugs were needed to inhibit immunocaptured respiratory complexes, supporting the contention that bioaccumulation is involved. The same rank order was found when monitoring mitochondrial membrane potential, ROS production, and glutathione levels in primary human hepatocytes. In toto, these data indicate that biguanide-induced lactic acidosis can be attributed to acceleration of glycolysis in response to mitochondrial impairment. Indeed, the desired clinical outcome, viz., decreased blood glucose, could be due to increased glucose uptake and glycolytic flux in response to drug-induced mitochondrial dysfunction.
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Metformin has only weak anti-proliferative activity against many cancer cell lines and patient-derived melanoma cells when nutrients are abundant.
“Metformin exerts only weak anti-proliferative effects on an array of cancer cell lines and patient-derived melanoma cells when cells are kept in nutrient-rich conditions (Figure S1A) (Dykens et al., 2008).”
From Combination of Hypoglycemia and Metformin Impairs Tumor Metabolic Plasticity and Growth by Modulating the PP2A-GSK3β-MCL-1 Axis (2019) · cites this paper as Dykens et al., 2008
The IC50 for metformin to inhibit mitochondrial complex 1 is 19-66 mM.
“It is also worthy of note that the IC50 for metformin to inhibit mitochondrial complex 1 is 19–66 mM (140, 141).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [140]
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“By interfering with mitochondrial respiration in the liver, they decrease gluconeogenesis (and lactate clearance) and may potentially increase glucose consumption (and lactate production) [10,12,13].”
BackgroundDrug induced mitochondrial dysfunction: Mechanisms and adverse clinical consequences
Vuda, M., & Kamath, A. (2016) · Mitochondrion · doi:10.1016/j.mito.2016.10.005 · Cited by 83 · see citing works
“…induced hepatotoxicity. caused by inhibition of membrane potential and mitochondrial respiratory complexes I and IV activity Study in human hepatocytes in vitro showed inhibition of membrane potential and mitochondrial respiratory complexes I and IV activity by nefazadone (Dykens et al., 2008a).”
BackgroundMetformin-Treated Patients With Type 2 Diabetes Have Normal Mitochondrial Complex I Respiration
Larsen, S., Rabøl, R., Hansen, C. N., Madsbad, S., Helge, J. W., & Dela, F. (2012) · Diabetologia · doi:10.1007/s00125-011-2340-0 · Cited by 81 · see citing works
“It has previously been suggested that metformin accumulates in the mitochondria [25], and therefore it cannot be completely ruled out that an accumulation of metformin can occur in human skeletal muscle mitochondria.”
BackgroundSelective Inhibition of Deactivated Mitochondrial Complex I by Biguanides
Matsuzaki, S., & Humphries, K. M. (2015) · Biochemistry · doi:10.1021/bi501473h · Cited by 81 · see citing works
A combined in vitro approach to improve the prediction of mitochondrial toxicants
Eakins, J. A., Bauch, C., Woodhouse, H. J., Park, B. J., Bevan, S. J., Dilworth, C., & Walker, P. (2016) · Toxicology in Vitro · doi:10.1016/j.tiv.2016.03.016 · Cited by 79 · see citing works
Mailloux, R. J., & Harper, M. (2010) · The FASEB Journal · doi:10.1096/fj.09-151803 · Cited by 80 · see citing works
“Several studies have shown that hepatocytes cultured in HG medium are more reliant on glycolysis to meet their energetic demands, whereas cells cultured in galactose medium utilize aerobic respiration and the TCA cycle to fulfill these needs (23, 24).”
BackgroundBridges, H. R., Sirviö, V. A., Agip, A.-N. A., & Hirst, J. (2016) · BMC Biology · doi:10.1186/s12915-016-0287-9 · Cited by 81 · see citing works
“Improved transmembrane diffusion as a result of their greater hydrophobicity has previously been suggested as a reason why phenformin and buformin are more potent inhibitors of cellular respiration than metformin [30], but our data explain that this correlation is observed because the more hydrophobic compounds are be…”
Szymczak-Pajor, I., Wenclewska, S., & Śliwińska, A. (2022) · Pharmaceuticals · doi:10.3390/ph15070810 · Cited by 81 · see citing works
Trimethoprim–metformin interaction and its genetic modulation by OCT 2 and MATE1 transporters
Grün, B., Kießling, M. K., Burhenne, J., Riedel, K., Weiß, J., Rauch, G., Haefeli, W. E., & Czock, D. (2013) · British Journal of Clinical Pharmacology · doi:10.1111/bcp.12079 · Cited by 77 · see citing works
Wang, Y., Du, L., Liang, X., Meng, P., Bi, L., Wang, Y., Wang, C., & Tang, B. (2018) · Hepatology · doi:10.1002/hep.30421 · Cited by 77 · see citing works
“The glucose-lowering drug, metformin, has been demonstrated to inhibit complex I of the mitochondria,(28) leading to increases in intracellular AMP and ADP that bind to the gamma regulatory subunit of AMPK and promote LKB1-mediated phosphorylation of AMPK.”
BackgroundTetracycline Antibiotics Induce Host-Dependent Disease Tolerance to Infection
Colaço, H. G., Barros, A., Neves‐Costa, A., Seixas, E., Pedroso, D. C. S., Velho, T. R., Willmann, K. L., Faísca, P., Grabmann, G., Yi, H., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.09.011 · Cited by 80 · see citing works
“To address the question of whether the induction of disease tolerance by ETC required general or specific perturbations of ETC complexes, we used the biguanide antidiabetic drug phenformin, a known potent inhibitor of complex I of the ETC (Dykens et al., 2008).”
MethodlncRNA NBR2 modulates cancer cell sensitivity to phenformin through GLUT1
Liu, X., & Gan, B. (2016) · Cell Cycle · doi:10.1080/15384101.2016.1249545 · Cited by 76 · see citing works
“Since our current study has focused on phenformin, it is important to emphasize that several lines of evidence strongly support the utility of phenformin in cancer treatment in the near future: first, phenformin is a much more potent inhibitor of mitochondrial complex I, with more than 50 fold greater potency, than me…”
BackgroundHynes, J., Nadanaciva, S., Swiss, R. L., Carey, C., Kirwan, S., & Will, Y. (2012) · Toxicology in Vitro · doi:10.1016/j.tiv.2012.11.002 · Cited by 74 · see citing works
Piel, S., Ehinger, J. K., Elmér, E., & Hansson, M. J. (2014) · Acta Physiologica · doi:10.1111/apha.12311 · Cited by 71 · see citing works
“…however, propose an interference of the drug with mitochondrial function being the key factor for both the primary therapeutic, glucose-lowering effect (El-Mir 2000, Owen et al. 2000) and the development of metformin-associated LA (Brunmair et al. 2004, Dykens et al. 2008, Protti et al. 2012b).”
BackgroundResultInfluentialMetformin overdose causes platelet mitochondrial dysfunction in humans
Protti, A., Lecchi, A., Fortunato, F., Artoni, A., Greppi, N., Vecchio, S., Fagiolari, G., Moggio, M. G., Comi, G. P., Mistraletti, G., et al. (2012) · Critical Care · doi:10.1186/cc11663 · Cited by 70 · see citing works
“their mitochondrial respiration [12-15].”
Yaribeygi, H., Atkin, S. L., & Sahebkar, A. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27754 · Cited by 68 · see citing works
“However, these are few in number and the majority of the proteins needed for the mitochondrial function are encoded by the host cell and are imported from the cytosol into the mitochondria (Elrod & Gustafsson, 2018).”
BackgroundMethodInfluentialDrug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions
Will, Y., Shields, J. E., & Wallace, K. B. (2019) · Biology · doi:10.3390/biology8020032 · Cited by 65 · see citing works
“Glucophage (metformin), which causes much less mitochondrial toxicity is widely used in the clinic and only in rare occasions causes lactic acidosis in most likely already predisposed patients [55].”
BackgroundMetformin overdose, but not lactic acidosis per se, inhibits oxygen consumption in pigs
Protti, A., Fortunato, F., Monti, M., Vecchio, S., Gatti, S., Comi, G. P., Giuseppe, R. D., & Gattinoni, L. (2012) · Critical Care · doi:10.1186/cc11332 · Cited by 64 · see citing works
“As a possible result, liver lactate output increases [11-13] and uptake decreases (along with gluconeogenesis) [12,14].”
BackgroundGranja, S., Marchiq, I., LeFloch, R., Moura, C. S., Baltazar, F., & Pouysségur, J. (2014) · Oncotarget · doi:10.18632/oncotarget.2862 · Cited by 64 · see citing works
Pharmacology of metformin – An update
Glossmann, H. H., & Lutz, O. M. D. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172782 · Cited by 61 · see citing works
Drug-Induced Inhibition of Mitochondrial Fatty Acid Oxidation and Steatosis
Massart, J., Begriche, K., Buron, N., Porceddu, M., Borgne‐Sanchez, A., & Fromenty, B. (2013) · Current Pathobiology Reports · doi:10.1007/s40139-013-0022-y · Cited by 54 · see citing works
Mitochondrial dysfunction induced by leflunomide and its active metabolite
Xuan, J., Ren, Z., Qing, T., Couch, L. H., Shi, L. M., Tolleson, W. H., & Guo, L. (2018) · Toxicology · doi:10.1016/j.tox.2018.02.003 · Cited by 53 · see citing works
“Inhibition of mitochondrial electron transport complexes underlies the mechanism of liver toxicity induced by a variety of mitochondrial toxicants (Dykens et al., 2008a, 2008b; Nadanaciva et al., 2007a, 2007b; Will et al., 2008).”
BackgroundMagno, L. D., Manni, S., Pastena, F. D., Coni, S., Macone, A., Cairoli, S., Sambucci, M., Infante, P., Moretti, M., Petroni, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.01.024 · Cited by 53 · see citing works
“The Antitumor Effect of Phenformin Is Mediated by mGPD-Dependent Changes of the Redox State Because biguanides are believed to exert most of their actions by inhibiting mitochondrial respiratory complex I (Dykens et al., 2008; El-Mir et al., 2000; Owen et al., 2000), we studied whether, under our experimental conditio…”
BackgroundCardionomics: a new integrative approach for screening cardiotoxicity of drug candidates
Gwathmey, J. K., Tsaioun, K., & Hajjar, R. J. (2009) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250902932915 · Cited by 52 · see citing works
“The metabolism of many cell lines is often anaerobic, by means of glycolysis, despite their having functional mitochondria and an adequate oxygen supply [21,22].”
BackgroundBiguanides drugs: Past success stories and promising future for drug discovery
Grytsai, O., Myrgorodska, I., Rocchi, S., Ronco, C., & Benhida, R. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113726 · Cited by 49 · see citing works
Ng, D. J. Y., Pasikanti, K. K., & Chan, E. C. Y. (2010) · Metabolomics · doi:10.1007/s11306-010-0250-7 · Cited by 50 · see citing works
Rana, P., Aleo, M. D., Wen, X., & Kogut, S. J. (2021) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2021.05.028 · Cited by 49 · see citing works
Tedong, L., Madiraju, P., Martineau, L. C., Vallerand, D., Arnason, J. T., Désiré, D. D. P., Lavoie, L., Kamtchouing, P., & Haddad, P. S. (2010) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201000045 · Cited by 49 · see citing works
Stein, B. D., Calzolari, D., Hellberg, K., Hu, Y., He, L., Hung, C., Toyama, E. Q., Ross, D. S., Lillemeier, B. F., Cantley, L. C., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.117 · Cited by 43 · see citing works
“…nature and extent of PKD and MK2 activation, we treated control or LKB1-liver-specific knockout mice with metformin as well as its more potent analog, phenformin, which has 100-fold higher inhibition of complex I and induces greater ROS as a result (Dykens et al., 2008; Shackelford et al., 2013).”
MethodHeightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers
Momcilovic, M., McMickle, R., Abt, E., Seki, A., Simko, S. A., Magyar, C., Stout, D. B., Fishbein, M. C., Walser, T. C., Dubinett, S. M., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0797 · Cited by 46 · see citing works
“Furthermore, phenformin actively induces a cellular switch to glycolytic metabolism (41, 42), which explains the expansion of FDG avid phenformin-resistant SCCs we observe in KLluc mice (Figs.”
Mitochondria-targeted metformins: anti-tumour and redox signalling mechanisms
Kalyanaraman, B., Cheng, G., Hardy, M., Ouari, O., Sikora, A., Zielonka, J., & Dwinell, M. B. (2017) · Interface Focus · doi:10.1098/rsfs.2016.0109 · Cited by 44 · see citing works
Chen, S., Wu, Q., Li, X., Li, D., Mei, N., Ning, B., Puig, M., Ren, Z., Tolleson, W. H., & Guo, L. (2021) · Journal of Environmental Science and Health, Part C · doi:10.1080/26896583.2021.1880242 · Cited by 44 · see citing works
Pharmacologically-Induced Metabolic Acidosis
Liamis, G. L., Milionis, H. J., & Elisaf, M. (2010) · Drug Safety · doi:10.2165/11533790-000000000-00000 · Cited by 45 · see citing works
Jiaojiao, H., Wang, K., Zheng, N., Qiu, Y., Xie, G., Su, M., Jia, W. P., & Li, H. (2015) · Scientific Reports · doi:10.1038/srep17423 · Cited by 43 · see citing works
The Tumor Suppressor Kinase LKB1: Metabolic Nexus
Bourouh, M., & Marignani, P. A. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.881297 · Cited by 43 · see citing works
“Metformin is used to treat type II diabetes and functions by inhibiting mitochondrial complex I of the ETC (ElMir et al., 2000; Dykens et al., 2008).”
BackgroundHitchings, A. W., Archer, J. R. H., Srivastava, S. A., & Baker, E. H. (2014) · COPD Journal of Chronic Obstructive Pulmonary Disease · doi:10.3109/15412555.2014.898052 · Cited by 42 · see citing works
“As in non-COPD cohorts in which there have been similar fi ndings (21, 22), this diff erence may be attributable to direct eff ects of metformin on mitochondrial function, or confounding by other variables such as body weight (22, 23).”
BackgroundMomcilovic, M., & Shackelford, D. B. (2017) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2017.220 · Cited by 42 · see citing works
“Conversely, KrasG12D driven tumors treated with biguanides, which are mitochondria complex I inhibitors that suppress oxidative phosphorylation (OXPHOS), induced up regulation of glycolysis as a compensatory mechanism that is readily detected by 18F-FDG PET imaging (Dykens et al., 2008; Shackelford et al., 2013).”
BackgroundImpact of 5'-amp-activated Protein Kinase on Male Gonad and Spermatozoa Functions
Nguyen, T. M. D. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00025 · Cited by 41 · see citing works
“Metformin and other biguanides, like phenformin (Dykens et al., 2008), activate AMPK by inhibiting Complex 1 of the respiratory chain, which, in turn, decreases intracellular ATP levels (Hardie, 2006; Hawley et al.”
BackgroundAMPK directly inhibits NDPK through a phosphoserine switch to maintain cellular homeostasis
Onyenwoke, R. U., Forsberg, L. J., Liu, L., Williams, T., Álzate, Ó., & Brenman, J. E. (2011) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-08-0699 · Cited by 39 · see citing works
Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species
Jeong, Y., & Jusko, W. J. (2021) · Pharmaceuticals · doi:10.3390/ph14060545 · Cited by 41 · see citing works
“, IC50 of 19–66 mM) [94,95], while the blood glucose lowering effect was mediated by increased mitochondrial respiration and fission at clinically relevant concentrations (e.”
BackgroundDeus, C. M., Zehowski, C., Nordgren, K. K. S., Wallace, K. B., Skildum, A. J., & Oliveira, P. J. (2015) · Toxicology · doi:10.1016/j.tox.2015.05.001 · Cited by 39 · see citing works
“In contrast to what we observed with cardiomyoblasts, hepatoma HepG2 cells cultured in the OXPHOS medium are usually more susceptible to mitochondrial toxins than cells grown in highglucose medium (Dykens et al., 2008; Marroquin et al., 2007; Rana et al., 2011).”
ResultBulterijs, S. (2011) · Rejuvenation Research · doi:10.1089/rej.2011.1153 · Cited by 37 · see citing works
Angioi, A., Cabiddu, G., Conti, M. E., Pili, G., Atzeni, A., Matta, V., Cao, R., Floris, M., Songini, M., Mulas, M. F., et al. (2018) · BMC Nephrology · doi:10.1186/s12882-018-0875-8 · Cited by 37 · see citing works
“This ultimately leads to a block in pyruvate metabolism and the excess pyruvate that cannot be managed by the mitochondria is transformed into lactate, especially within the liver, intestine and, to a lesser extent, in other tissues [23, 24].”
BackgroundMarín‐Hernández, Á., Gallardo‐Pérez, J. C., López‐Ramírez, S. Y., García-García, J. D., Rodríguez‐Zavala, J. S., Ruíz-Azuara, L., Gracia‐Mora, I., Zentella‐Dehesa, A., Sosa‐Garrocho, M., Macías‐Silva, M., et al. (2012) · Archives of Toxicology · doi:10.1007/s00204-012-0809-3 · Cited by 36 · see citing works
“…(HepG2) cells exposed to anti-hyperglycemic drugs such as biguanides (buformin, phenformin), nefazodone (antidepressant), or the alkaloid berberine (Dykens et al. 2008a, b; Yin et al. 2008), it has been shown that glycogenolysis Xux increases by inducing mitochondrial dysfunction (and hence…”
AMP-activated protein kinase and energy balance in breast cancer.
Zhao, H., Orhan, Y. C., Zha, X., Esencan, E., Chatterton, R. T., & Bulun, S. E. (2017) · Europe PMC (PubMed Central) · Cited by 34 · see citing works
Mitochondrial targets of metformin—Are they physiologically relevant?
Pecinová, A., Brázdová, A., Drahota, Z., Houštěk, J., & Mráček, T. (2019) · BioFactors · doi:10.1002/biof.1548 · Cited by 33 · see citing works
“The reported IC50 for metformin on complex I activity are extremely high and range from 20 to 80 mmol/L.(33,38,40) Moreover, the specific site of metformin binding to the complex I remains elusive as it was shown to influence both flavin and ubiquinone-”
BackgroundMoonira, T., Chachra, S. S., Ford, B. E., Marín, S., Alshawi, A., Adam-Primus, N. S., Arden, C., Al‐Oanzi, Z. H., Foretz, M., Viollet, B., et al. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012533 · Cited by 34 · see citing works
“Depolarization of mitochondria by low metformin has been reported (45).”
BackgroundMetformin Biodistribution: A Key to Mechanisms of Action?
Sundelin, E. I. O., Jensen, J., Jakobsen, S., Gormsen, L. C., & Jessen, N. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa332 · Cited by 33 · see citing works
Cantoria, M. J., Boros, L. G., & Meuillet, E. J. (2013) · Metabolomics · doi:10.1007/s11306-013-0555-4 · Cited by 32 · see citing works
“Metabolic downstream targets of metformin involve the electron transport chain (ETC) complex I (WhitakerMenezes et al. 2011; Gonzalez-Barroso et al. 2012; Dykens et al. 2008), which results in energy depletion in cancer cells.”
BackgroundLiu, C., Sekine, S., & Ito, K. (2016) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2016.04.010 · Cited by 32 · see citing works
Glucose Metabolism in Burns—What Happens?
Bădoiu, S. C., Miricescu, D., Stănescu-Spînu, I.-I., Totan, A., Badoiu, S. E., Costagliola, M., & Greabu, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105159 · Cited by 33 · see citing works
Heishima, K., Sugito, N., Soga, T., Nishikawa, M., Ito, Y., Honda, R. P., Kuranaga, Y., Sakai, H., Ito, R., Nakagawa, T., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci139933 · Cited by 32 · see citing works
“, biguanides, such as metformin and phenformin (11, 12), or high toxicity, e.”
BackgroundMetformin-Associated Acute Kidney Injury and Lactic Acidosis
Arroyo, D., Melero, R., Panizo, N., Goicoechea, M., Benítez, P. R., de Vinuesa, S. G., Verde, E., Tejedor, A., & Luño, J. (2011) · International Journal of Nephrology · doi:10.4061/2011/749653 · Cited by 32 · see citing works
Bastian, A., Thorpe, J. E., Disch, B. C., Bailey‐Downs, L. C., Gangjee, A., Devambatla, R. K. V., Henthorn, J., Humphries, K. M., Vadvalkar, S. S., & Ihnat, M. A. (2015) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.114.220335 · Cited by 31 · see citing works
“Galactose drives cells to upregulate energy production through oxidative phosphorylation in the mitochondria, making them more suitable for studying drug-induced mitochondrial dysfunction (Dykens et al., 2008; Aguer et al., 2011).”
BackgroundMonogenic Diabetes: A Diagnostic Algorithm for Clinicians
Carroll, R. W., & Murphy, R. (2013) · Genes · doi:10.3390/genes4040522 · Cited by 31 · see citing works
Current Concepts in Drug‐Induced Mitochondrial Toxicity
Nadanaciva, S., & Will, Y. (2009) · Current Protocols in Toxicology · doi:10.1002/0471140856.tx0215s40 · Cited by 31 · see citing works
- Authors
- Dykens, J. A., Jamieson, J., Marroquin, L., Nadanaciva, S., Billis, P. A., & Will, Y.
- Affiliations
- Pfizer (United Kingdom) (GB)
- Pfizer (United States) (US)
- Corresponding author
- Dykens, James A.
- Venue
- Toxicology and Applied Pharmacology
- Publisher
- Elsevier BV
- Published
- 2008-12
- Volume
- 233
- Issue
- 2
- Pages
- 203-210
- ISSN
- 0041-008X (ISSN-L)
- OpenAlex
- W1997224005
- Cited by
- 220
- References
- 35
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 14 · 2021: 17 · 2020: 13 · 2019: 16 · 2018: 19 · 2017: 11 · 2016: 15 · 2015: 12 · 2014: 17 · 2013: 9 · 2012: 15
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Toxicology and Applied Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- biguanides, metformin, buformin, phenformin, mitochondrial dysfunction, lactic acidosis, hepatotoxicity, HepG2 cells, human hepatocytes, galactose metabolism, mitochondrial respiration, mitochondrial membrane potential, reactive oxygen species, glutathione, glycolysis, cytotoxicity, drug-induced liver injury
- MeSH terms
- Acidosis, Lactic, Animals, Blood Glucose, Buformin, Cell Line, Cell Survival, Culture Media, Glutathione, Glycolysis, Humans, Hypoglycemic Agents, Male, Metformin, Mitochondria, Liver, Oxidation-Reduction, Phenformin, Rats, Sprague-Dawley, Reactive Oxygen Species, Cell Respiration, Lactic Acid, Hepatocytes, Rats, Membrane Potential, Mitochondrial
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