Co‐Metabolism of Ethanol, Ethanol‐Derived Acetaldehyde, and 4‐Hydroxynonenal in Isolated Rat Hepatocytes
Open accessAbstract
Our laboratory has previously reported on the ability of 4‐hydroxynonenal (4‐HNE), a primary product of lipid peroxidation, to inhibit acetaldehyde metabolism in isolated mouse liver mitochondria. The purpose of the present study is to determine whether the co‐metabolism of ethanol and 4‐HNE compromises the elimination of either substrate in isolated rat hepatocytes. Hepatocytes were isolated and incubated with ethanol and 4‐HNE. Ethanol elimination and acetaldehyde accumulation were monitored by gas chromatography, whereas 4‐HNE elimination and metabolite accumulation were measured by UV detection and reversed‐phase HPLC at 202 nm. In the absence of 4‐HNE, hepatocytes metabolized ethanol at an initial rate of 9.4 nmol/min/million cells. Ethanol elimination was moderately inhibited by the presence of 4‐HNE. Accumulation of ethanol‐derived acetaldehyde was not apparent in incubations with only ethanol. In contrast, in incubations containing both substrates, ethanol‐derived acetaldehyde accumulation exceeded that observed in hepatocytes exposed only to ethanol and was proportional to the 4‐HNE concentration in the incubations. In all instances, the rate of 4‐HNE elimination was not compromised by the presence of ethanol. Accordingly, ethanol metabolism did not alter the oxidative or conjugative metabolism of 4‐HNE. However, the reductive metabolism of 4‐HNE was affected by the presence of ethanol, wherein accumulation of 1,4‐dihydroxy‐2‐nonene increased >2‐fold of that observed in incubations with only 4‐HNE. To determine further if 4‐HNE and ethanol are metabolized through the same metabolic pathways, cells were preincubated with either 4‐methylpyrazole or cyanamide to inhibit alcohol dehydrogenase (E.C. 1.1.1.1.) and aldehyde dehydrogenase (E.C. 1.2.1.2.), respectively. Expectantly, 4‐methylpyrazole blocked the formation of 1,4‐dihydroxy‐2‐nonene, but had no effect on the rate of 4‐HNE elimination. In contrast, cyanamide substantially inhibited the formation of 4‐hydroxy‐2‐nonenoic acid, decreased the rate of 1,4‐dihydroxy‐2‐nonene formation, but did not decrease the elimination rate of 4‐HNE. Overall, these results support our previous observation that 4‐HNE inhibits acetaldehyde metabolism and establish that ethanol and 4‐HNE are metabolized through the same alcohol dehydrogenase‐ and aldehyde dehydrogenase‐mediated pathways. These data continue to suggest that, as a consequence of enhanced lipid peroxidation resulting from chronic ethanol consumption, increased 4‐HNE levels could compromise cellular elimination of ethanol‐derived acetaldehyde and thus function in the potentiation of alcoholic liver fibrosis.
Integrity signals
Registry
Cites
Statistics
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?
MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.
“MDA and 4-HNE are reactive lipid peroxides with short half-lives that can form covalent adducts with various proteins and nucleic acids in the body.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [177]
Ethanol intake can induce 4-HNE to interact with mitochondrial, ER, and cytosolic proteins, inactivating them and resulting in accumulation of lipid aldehydes, ER stress, mitochondrial dysfunction, cell signaling alteration, and potentially multitissue injury.
“For instance, ethanol intake can induce 4-HNE to interact with cytochrome C oxidase (complex IV) and ALDH2 in the mitochondria, GRP78 and disulfide isomerase in the ER, and ERK1/2, phosphatase and tensin homolog (PTEN), AMP-activated protein kinase (AMPK), and gamma-glutamylcysteine synthetase (GCS) in the cytosol.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [177]
Excessive alcohol exposure increases oxidative stress and levels of reactive acetaldehyde and lipid aldehydes with simultaneous decrease in defensive molecules and detoxification enzymes including GSH and ALDH2, leading to accumulation of acetaldehyde adducts and possibly AGEs in the brain, which has a much lower detoxification capacity than the liver.
“Excessive alcohol exposure increases oxidative stress and the levels of reactive acetaldehyde and lipid aldehydes with a simultaneous decrease in defensive molecules and detoxification enzymes, including GSH and ALDH253,172,177.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [177]
Cites
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90192-6 · Cited by 6,672 · see citing works
[4] Isolation and use of liver cells
Moldéus, P., Högberg, J., & Orrenius, S. (1978) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(78)52006-5 · Cited by 1,223 · see citing works
Reed, D. J., Babson, J. R., Beatty, P. W., Brodie, A. E., Ellis, W. W., & Potter, D. W. (1980) · Analytical Biochemistry · doi:10.1016/0003-2697(80)90118-9 · Cited by 1,178 · see citing works
Korsten, M. A., Matsuzaki, S., Feinman, L., & Lieber, C. S. (1975) · New England Journal of Medicine · doi:10.1056/nejm197502202920802 · Cited by 518 · see citing works
Experimental liver cirrhosis induced by alcohol and iron.
Tsukamoto, H., Horne, W., Kamimura, S., Niemelä, O. J., Parkkila, S., Ylä‐Herttuala, S., & Brittenham, G. M. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118077 · Cited by 512 · see citing works
4‐Hydroxyalk‐2‐enals are substrates for glutathione transferase
Ålin, P., Danielson, U. H., & Mannervik, B. (1985) · FEBS Letters · doi:10.1016/0014-5793(85)80532-9 · Cited by 421 · see citing works
Poli, G., Mu, D., Cheeseman, K. H., Slater, T. F., Lang, J., & Esterbauer, H. (1985) · Biochemical Journal · doi:10.1042/bj2270629 · Cited by 360 · see citing works
Immunochemical detection of 4-hydroxynonenal protein adducts in oxidized hepatocytes.
Uchida, K., Szweda, L. I., Chae, H. Z., & Stadtman, E. R. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.18.8742 · Cited by 332 · see citing works
Reaction of Glutathione with Conjugated Carbonyls
Esterbauer, H., Zöllner, H., & Scholz, N. (1975) · Zeitschrift für Naturforschung C · doi:10.1515/znc-1975-7-808 · Cited by 265 · see citing works
Hartley, D. P., Ruth, J. A., & Petersen, D. R. (1995) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1995.1028 · Cited by 243 · see citing works
Self-citationFernández-Checa, J. C., García‐Ruiz, C., Ookhtens, M., & Kaplowitz, N. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115010 · Cited by 242 · see citing works
Esterbauer, H., Zöllner, H., & Lang, J. (1985) · Biochemical Journal · doi:10.1042/bj2280363 · Cited by 236 · see citing works
Kamimura, S., Gaal, K. K., Britton, R. S., Bacon, B. R., Triadafilopoulos, G., & Tsukamoto, H. (1992) · Hepatology · doi:10.1002/hep.1840160225 · Cited by 234 · see citing works
Hirano, A., Kaplowitz, N., Tsukamoto, H., Kamimura, S., & Fernández-Checa, J. C. (1992) · Hepatology · doi:10.1002/hep.1840160619 · Cited by 232 · see citing works
Boleda, M. D., Saubi, N., Farrés, J., & Parés, X. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1564 · Cited by 213 · see citing works
Functional Compartmentation of Acetaldehyde Oxidation in Rat Liver
Parrilla, R., Ohkawa, K., Lindros, K. O., Zimmerman, U. P., Kobayashi, K., & WILLIAMSON, J. R. (1974) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42410-1 · Cited by 192 · see citing works
Ishikawa, T., Esterbauer, H., & Sies, H. (1986) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)35978-1 · Cited by 185 · see citing works
In vivo formation of a free radical metabolite of ethanol.
Knecht, K. T., Bradford, B. U., Mason, R. P., & Thurman, R. G. (1990) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)09446-5 · Cited by 166 · see citing works
Cytotoxic aldehydes originating from the peroxidation of liver microsomal lipids
Benedetti, A., Comporti, M., Fulceri, R., & Esterbauer, H. (1984) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(84)90219-4 · Cited by 146 · see citing works
Mitchell, D., & Petersen, D. R. (1987) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(87)90245-6 · Cited by 130 · see citing works
Self-citationFernández-Checa, J. C., Ookhtens, M., & Kaplowitz, N. (1987) · Journal of Clinical Investigation · doi:10.1172/jci113063 · Cited by 126 · see citing works
Cederaum, A. I. (1989) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(89)90033-6 · Cited by 104 · see citing works
Pharmacokinetics: Processes and Mathematics
Welling, P. G. (1986) · Medical Entomology and Zoology · Cited by 101 · see citing works
Fernández-Checa, J. C., Ookhtens, M., & Kaplowitz, N. (1989) · Journal of Clinical Investigation · doi:10.1172/jci114008 · Cited by 95 · see citing works
Grune, T., Wg, S., Zöllner, H., & Esterbauer, H. (1994) · PubMed · Cited by 92 · see citing works
Valerio, L. G., Parks, W. T., & Petersen, D. R. (1996) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1996.tb01134.x · Cited by 89 · see citing works
Self-citationShaw, S., Jayatilleke, E., & Lieber, C. S. (1988) · Alcohol · doi:10.1016/0741-8329(88)90010-9 · Cited by 88 · see citing works
Reinke, L. A., Kotake, Y., McCay, P. B., & Janzen, E. G. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90185-6 · Cited by 80 · see citing works
THE ROLE OF ALCOHOLISM IN HEPATIC IRON STORAGE DISEASE*
Powell, L. W. (1975) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1975.tb19149.x · Cited by 74 · see citing works
Hepatic Mitochondrial Malondialdehyde Metabolism in Rats With Chronic Iron Overload
Britton, R. S., O’Neill, R., & Bacon, B. R. (1990) · Hepatology · doi:10.1002/hep.1840110116 · Cited by 69 · see citing works
Lipid peroxidation, iron mobilization and radical generation induced by alcohol
Shaw, S. (1989) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(89)90030-0 · Cited by 65 · see citing works
Mitchell, D. (1991) · Hepatology · doi:10.1016/0270-9139(91)92572-p · Cited by 53 · see citing works
Ethanol-induced iron mobilization: Role of acetaldehyde-aldehyde oxidase generated superoxide
Shaw, S., & Jayatilleke, E. (1990) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(90)90044-j · Cited by 46 · see citing works
Subcellular site of acetaldehyde oxidation in rat liver
Corrall, R. J. M., Havre, P. A., Margolis, J. M., Kong, M.-S., & Landau, B. R. (1976) · Biochemical Pharmacology · doi:10.1016/0006-2952(76)90166-0 · Cited by 34 · see citing works
Grune, T., Siems, W., Kowalewski, J., Zöllner, H., & Esterbauer, H. (1991) · PubMed · Cited by 33 · see citing works
Effects of Alcohol, Carbon Tetrachloride, and Choline Deficiency on Iron Metabolism in the Rat
Batey, R. G., & Johnston, R. (1993) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.1993.tb05643.x · Cited by 22 · see citing works
Effect of chronic ethanol administration on iron metabolism in the rat
Sánchez, J. A., Casas, M., & Rama, R. (1988) · European Journal Of Haematology · doi:10.1111/j.1600-0609.1988.tb00204.x · Cited by 22 · see citing works
Hjelle, J. J., Grubbs, J. H., Beer, D. G., & Petersen, D. R. (1983) · Toxicology and Applied Pharmacology · doi:10.1016/0041-008x(83)90220-x · Cited by 19 · see citing works
Self-citationSiems, W. G., Zoliner, H., & Esterbauer, H. (1990) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(90)90564-y · Cited by 17 · see citing works
Mitchell, D. Y., & Petersen, D. R. (1991) · Hepatology · doi:10.1002/hep.1840130420 · Cited by 10 · see citing works
Self-citationCovalent Modification of Class 2 and Class 3 Aldehyde Dehydrogenase by 4-Hydroxynonenal
Hartley, D. P., Lindahl, R. G., & Petersen, D. R. (1995) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-1965-2_13 · Cited by 8 · see citing works
Self-citationHartley, D. P., & Petersen, D. R. (1993) · Advances in experimental medicine and biology · doi:10.1007/978-1-4615-2904-0_4 · Cited by 7 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Rungratanawanich, W., Qu, Y., Wang, X., Essa, M. M., & Song, B.-J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00561-7 · Cited by 411 · see citing works
The Role of Acetaldehyde in the Actions of Alcohol (Update 2000)
Eriksson, C. J. P. (2001) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2001.tb02369.x · Cited by 235 · see citing works
The Role of Acetaldehyde in the Actions of Alcohol (Update 2000)
Eriksson, C. J. P. (2001) · Alcoholism Clinical and Experimental Research · doi:10.1097/00000374-200105051-00005 · Cited by 205 · see citing works
Hamblin, M., Friedman, D. B., Hill, S., Caprioli, R. M., Smith, H., & Hill, M. F. (2007) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2006.12.018 · Cited by 120 · see citing works
Shiva, S., Oh, J.-Y., Landar, A. L., Ulasova, E., Venkatraman, A., Bailey, S. M., & Darley-Usmar, V. M. (2005) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.10.037 · Cited by 112 · see citing works
Galligan, J. J., McCullough, R. L., Shearn, C. T., Fritz, K. S., Backos, D. S., Jiang, H., Franklin, C. C., Orlicky, D. J., Maclean, K. N., & Petersen, D. R. (2012) · Journal of Toxicology · doi:10.1155/2012/207594 · Cited by 101 · see citing works
Self-citationShearn, C. T., Smathers, R. L., Backos, D. S., Reigan, P., Orlicky, D. J., & Petersen, D. R. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.07.011 · Cited by 69 · see citing works
Self-citationSampey, B. P., Stewart, B. J., & Petersen, D. R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610602200 · Cited by 64 · see citing works
Self-citationSampey, B. P., Carbone, D. L., Doorn, J. A., Drechsel, D. A., & Petersen, D. R. (2006) · Molecular Pharmacology · doi:10.1124/mol.106.029686 · Cited by 64 · see citing works
Self-citationShearn, C. T., McCullough, R. L., Stewart, B. J., Fritz, K. S., Galligan, J. J., Hail, N., & Petersen, D. R. (2011) · Molecular Pharmacology · doi:10.1124/mol.110.069534 · Cited by 51 · see citing works
Self-citationSusceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver
McCullough, R. L., Galligan, J. J., Shearn, C. T., Fritz, K. S., Mercer, K. E., Ronis, M. J. J., Orlicky, D. J., Davidson, N. O., & Petersen, D. R. (2013) · Journal of Lipid Research · doi:10.1194/jlr.m034892 · Cited by 46 · see citing works
Self-citationSergent, O., Griffon, B., Cillard, P., & Cillard, J. (2001) · Pathologie Biologie · doi:10.1016/s0369-8114(01)00244-9 · Cited by 38 · see citing works
Reichard, J. F., Vasiliou, V., & Petersen, D. R. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/s1388-1981(00)00095-0 · Cited by 33 · see citing works
Self-citationALDH2/ADH2 Polymorphism Associated with Vasculopathy and Neuropathy in Type 2 Diabetes
Suzuki, Y., Taniyama, M., Muramatsu, T., Higuchi, S., Ohta, S., Atsumi, Y., & Matsuoka, K. (2004) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2004.tb03227.x · Cited by 29 · see citing works
Sequence Tagging Reveals Unexpected Modifications in Toxicoproteomics
Dasari, S., Chambers, M., Codreanu, S. G., Liebler, D. C., Collins, B. C., Pennington, S. R., Gallagher, W. M., & Tabb, D. L. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100275t · Cited by 28 · see citing works
ALDH2/ADH2 Polymorphism Associated with Vasculopathy and Neuropathy in Type 2 Diabetes
Suzuki, Y., Taniyama, M., Muramatsu, T., Higuchi, S., Ohta, S., Atsumi, Y., & Matsuoka, K. (2004) · Alcoholism Clinical and Experimental Research · doi:10.1097/01.alc.0000133583.44581.99 · Cited by 25 · see citing works
Gallagher, E. P., Huisden, C. M., & Gardner, J. L. (2007) · Toxicology in Vitro · doi:10.1016/j.tiv.2007.04.004 · Cited by 25 · see citing works
Gallagher, E. P., & Gardner, J. L. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)01017-1 · Cited by 20 · see citing works
Murata, C., Taniyama, M., Kuriyama, S., Muramatsu, T., Atsumi, Y., Matsuoka, K., & Suzuki, Y. (2004) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2003.11.022 · Cited by 18 · see citing works
CYP2E1, Oxidative Stress, Post-translational Modifications and Lipid Metabolism
Lakshman, M., Garige, M., Gong, M., Leckey, L. C., Varatharajalu, R., Redman, R. S., Seth, D., Haber, P., Hirsch, K. R., AMDUR, R. L., et al. (2013) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-94-007-5881-0_7 · Cited by 15 · see citing works
Garige, M., Gong, M., Rao, M. N., Zhang, Y., & Lakshman, M. (2005) · Metabolism · doi:10.1016/j.metabol.2004.12.018 · Cited by 11 · see citing works
Gardner, J. L., Doi, A. M., Pham, R. T., Huisden, C. M., & Gallagher, E. P. (2003) · Toxicology and Applied Pharmacology · doi:10.1016/s0041-008x(03)00220-5 · Cited by 7 · see citing works
Suzuki, Y., Taniyama, M., Muramatsu, T., Ohta, S., Atsumi, Y., & Matsuoka, K. (2003) · Diabetes Care · doi:10.2337/diacare.26.1.249 · Cited by 6 · see citing works
Suzuki, Y., Kuriyama, S., Atsumi, Y., Murata, C., Matsuoka, K., Suzuki, Y., Taniyama, M., Muramatsu, T., Suzuki, Y., & Ohta, S. (2003) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(03)00020-2 · Cited by 5 · see citing works
Navid, A., Ng, D. M., Stewart, B. J., Wong, S., & Lightstone, F. C. (2013) · In Silico Pharmacology · doi:10.1186/2193-9616-1-14 · Cited by 4 · see citing works
Diabetic Vasculopathy and Alcohol Tolerance Trait in Type 2 Diabetes
Suzuki, Y., Taniyama, M., Muramatsu, T., Higuchi, S., Ohta, S., Atsumi, Y., & Matsuoka, K. (2003) · Diabetes Care · doi:10.2337/diacare.26.1.246 · Cited by 4 · see citing works
Heavy alcohol use exacerbates skeletal myopathy in peripheral artery disease
Koutakis, P., Fletcher, E., Papoutsi, E., Bohannon, W. T., Pipinos, I. I., Miserlis, D., & Pacher, P. (2025) · GeroScience · doi:10.1007/s11357-025-01965-3 · Cited by 1 · see citing works
Ocular Metabolism and Disposition of 4-Hydroxy-2-nonenal
Black, W., & Vasiliou, V. (2005) · Cutaneous and Ocular Toxicology · doi:10.1080/15569520500278906 · Cited by 1 · see citing works
Health, L., & Potter, B. J. (2015) · doi:10.24966/adsd-9594/100002 · Cited by 1 · see citing works
Viitala, K. (1998) · Cited by 1 · see citing works
- Authors
- Hartley, D. P., & Petersen, D. R.
- Affiliations
- University of Colorado Health (US)
- Corresponding author
- Petersen, Dennis R.
- ORCID
- Hartley, Dylan P.
- Venue
- Alcoholism: Clinical and Experimental Research
- Publisher
- Wiley
- Published
- 1997-04
- Volume
- 21
- Issue
- 2
- Pages
- 298-304
- ISSN
- 0145-6008 (ISSN-L)
- 1530-0277
- OpenAlex
- W2146392197
- Cited by
- 30
- References
- 41
- Citations by year
- 2025: 1 · 2021: 1 · 2015: 1 · 2013: 4 · 2012: 1
- FWCI
- 0.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Alcoholism Clinical and Experimental Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f31aa005370-02, 5p30dk034914-10)
- National Institute on Alcohol Abuse and Alcoholism (AA-09300, AA 05370)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-34914)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- 4-hydroxynonenal, alcohol metabolism, acetaldehyde accumulation, cometabolism, hepatocytes, lipid peroxidation, alcohol dehydrogenase inhibition, aldehyde dehydrogenase inhibition, 4-methylpyrazole, cyanamide
- MeSH terms
- Acetaldehyde, Alcohol Dehydrogenase, Ethanol, Aldehyde Dehydrogenase, Aldehydes, Animals, Cells, Cultured, Chromatography, Gas, Chromatography, High Pressure Liquid, Liver, Liver Cirrhosis, Alcoholic, Male, Metabolic Clearance Rate, Lipid Peroxidation, Rats, Sprague-Dawley, Mice, Rats
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
