The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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
In the citing paper
“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]
Citations
Cites
OWEN, M. R., DORAN, E., & HALESTRAP, A. P. (2000) · Biochemical Journal · doi:10.1042/bj3480607 · Cited by 2,157
Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D., & Will, Y. (2007) · Toxicological Sciences · doi:10.1093/toxsci/kfm052 · Cited by 632
Mitochondria as a Pharmacological Target
Szewczyk, A. M., & Wojtczak, L. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.1.101 · Cited by 544
Thiazolidinediones, Like Metformin, Inhibit Respiratory Complex I
Brunmair, B., Staniek, K., Gras, F., Scharf, N., Althaym, A., Clara, R., Roden, M., Gnaiger, E., Nohl, H., Waldhäusl, W., et al. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1052 · Cited by 521
Smith, A. L. (1967) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(67)10016-5 · Cited by 460
The significance of mitochondrial toxicity testing in drug development
Dykens, J. A., & Will, Y. (2007) · Drug Discovery Today · doi:10.1016/j.drudis.2007.07.013 · Cited by 419
Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity
Boelsterli, U. (2003) · Toxicology and Applied Pharmacology · doi:10.1016/s0041-008x(03)00368-5 · Cited by 403
Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice
Huang, X., Wullschleger, S., Shpiro, N., McGuire, V. A., Sakamoto, K., Woods, Y. L., Mcburnie, W., Fleming, S., & Alessi, D. R. (2008) · Biochemical Journal · doi:10.1042/bj20080557 · Cited by 396
Batandier, C., Guigas, B., Detaille, D., El-Mir, M., Fontaine, E., Rigoulet, M., & Leverve, X. M. (2006) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-006-9003-8 · Cited by 279
Detaille, D., Guigas, B., Chauvin, C., Batandier, C., Fontaine, E., Wiernsperger, N., & Leverve, X. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2179 · Cited by 263
Flagged first, then by citations
Research works printed but not linked: 1
- Irsigler, 1979, Biguanide-induced and -associated lactic acidosis: serum and tissue biguanide levels in hyperlactaemia and lactic acidosis, Wien. Klin. Wochenschr., 91, 59
Cited by
Sorted by citations
Items 201–219 of 219
Effects of metformin on human monocytic THP-1 cells - Implications for type 2 diabetes mellitus
Tsuei, A.-C. (2010) · Research Commons (University of Waikato)
The effects of hyperglycemia on glucose metabolism in epithelial ovarian cancer
Kellenberger, L. D. (2016) · The Atrium (University of Guelph)
Cerebral Mitochondrial Dysfunction and the Development of Targeted Therapeutics
Karlsson, M. (2017) · Lund University Publications (Lund University)
Metabolic and Morphologic Shifts in Neuro2a Cells Cultured in Galactose Medium
Welker, L. (2017) · The Keep (Eastern Illinois University)
The Evolution of Mitochondrial Toxicity Assessment in Industry
Hynes, J., & Will, Y. (2018) · Springer eBooks · doi:10.1007/978-3-319-73344-9_15
Measurement of Oxygen MetabolismIn Vivo
van Diemen, M. P. J., Ubbink, R., Münker, F. M., Mik, E. G., & Groeneveld, G. J. (2018) · Wiley eBooks · doi:10.1002/9781119329725.ch20
Simon, M., Baudry, T., Hernu, R., Cour, M., & Argaud, L. (2019) · Médecine Intensive Réanimation · doi:10.3166/rea-2019-0127
Rana, P. (2020) · Digital Commons - URI (University of Rhode Island) · doi:10.23860/rana-payal-2020
Novel compounds inhibiting HIV infection, breast cancer metastasis, and bacterial growth
Shepard, J. B. (2012) · Montana State University ScholarWorks (Montana State University)
Phenformin increases early hematopoietic progenitors in the Jak2V617F murine model
Alves-Silva, A. B., Fenerich, B. A., Fonseca, N. P., Fernandes, J. C., Coelho-Silva, J. L., Pereira‐Martins, D. A., Bianco, T. M., Scheucher, P. S., Rego, E. M., Chahud, F., et al. (2022) · Investigational New Drugs · doi:10.1007/s10637-022-01212-y · Cited by 1
“Both metformin and phenformin act in the mitochondria by inhibiting the complex I and by increasing the ratio of AMP/ATP, resulting in the activation of AMPK, which exerts antineoplastic activity in several cancer types [9, 11].”
BackgroundChandel, N. S. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.736825985.793567150
Paneque, A. A. E., Ortiz, M. G. C., Maldonado, E. A. D., Matute, S. G. U., Martínez, C. E. C., & Llumiquinga, P. M. Q. (2022) · doi:10.58594/dzdk6465
The role of PKD in mitochondrial fission during mitosis
Bielska, O. (2018) · theses.fr (ABES) · doi:10.70675/2dbab59fze200z4e37z9770zea1c8f1345ea
Grytsai, O. (2018) · theses.fr (ABES) · doi:10.70675/acf05fbfz122cz414fz8335zd2e0bce8fbbd
Marcucci, F., & Rumio, C. (2026) · Cell Signaling Inflammation & Disease · doi:10.1186/s44505-026-00005-x
“This, in turn, leads to the compensatory upregulation of fermentative glycolysis [20, 38], which is at the origin of the most dangerous side effect of metformin, lactic acidosis [21].”
UNDERSTANDING THE ROLE OF SUMOYLATION IN REGULATING LKB1 FUNCTION
Ritho, J. (2015) · Digital Commons-TMC (Texas Medical Center)
Metadata
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
