Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant

Nam On Ku, Sara A. Michie, Roy M. Soetikno, Evelyn Z. Resurreccion, Rosemary L. Broome, Robert G. Oshima, M. Bishr Omary

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Keratins 8 and 18 (K8/18) are intermediate filament phosphoglycoproteins that are expressed preferentially in simpletype epithelia. We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary, 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption. Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25% wt/wt of diet). The predisposition to hepatotoxicity results directly from the keratin mutation since nontransgenic or transgenic mice that express normal human K18 are more resistant. Hepatotoxicity was manifested by a significant difference in lethality, liver histopathology, and biochemical serum testing. Keratin glycosylation decreased in all griseofulvin-fed mice, whereas keratin phosphorylation increased dramatically preferentially in mice expressing normal K18. The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy. Our results indicate that hepatocyte intermediate filament disruption renders mice highly susceptible to hepatotoxicity, and raises the possibility that K18 mutations may predispose to drug hepatotoxicity. The dramatic phosphorylation increase in nonmutant keratins could provide survival advantage to hepatocytes.

Original languageEnglish
Pages (from-to)1034-1046
Number of pages13
JournalJournal of Clinical Investigation
Volume98
Issue number4
DOIs
Publication statusPublished - 1996 Aug 15

Fingerprint

Keratin-18
Transgenic Mice
Keratins
Griseofulvin
Hepatocytes
Intermediate Filaments
Phosphorylation
Keratin-8
Mutation
Hepatectomy
Chronic Hepatitis
Acetaminophen
Glycosylation
K-18 conjugate
Epithelium
Eating
Diet
Survival
Liver
Serum

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Ku, N. O., Michie, S. A., Soetikno, R. M., Resurreccion, E. Z., Broome, R. L., Oshima, R. G., & Omary, M. B. (1996). Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. Journal of Clinical Investigation, 98(4), 1034-1046. https://doi.org/10.1172/JCI118864
Ku, Nam On ; Michie, Sara A. ; Soetikno, Roy M. ; Resurreccion, Evelyn Z. ; Broome, Rosemary L. ; Oshima, Robert G. ; Omary, M. Bishr. / Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 4. pp. 1034-1046.
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abstract = "Keratins 8 and 18 (K8/18) are intermediate filament phosphoglycoproteins that are expressed preferentially in simpletype epithelia. We recently described transgenic mice that express point-mutant human K18 (Ku, N.-O., S. Michie, R.G. Oshima, and M.B. Omary, 1995. J. Cell Biol. 131:1303-1314) and develop chronic hepatitis and hepatocyte fragility in association with hepatocyte keratin filament disruption. Here we show that mutant K18 expressing transgenic mice are highly susceptible to hepatotoxicity after acute administration of acetaminophen (400 mg/Kg) or chronic ingestion of griseofulvin (1.25{\%} wt/wt of diet). The predisposition to hepatotoxicity results directly from the keratin mutation since nontransgenic or transgenic mice that express normal human K18 are more resistant. Hepatotoxicity was manifested by a significant difference in lethality, liver histopathology, and biochemical serum testing. Keratin glycosylation decreased in all griseofulvin-fed mice, whereas keratin phosphorylation increased dramatically preferentially in mice expressing normal K18. The phosphorylation increase in normal K18 after griseofulvin feeding appears to involve sites that are different to those that increase after partial hepatectomy. Our results indicate that hepatocyte intermediate filament disruption renders mice highly susceptible to hepatotoxicity, and raises the possibility that K18 mutations may predispose to drug hepatotoxicity. The dramatic phosphorylation increase in nonmutant keratins could provide survival advantage to hepatocytes.",
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Ku, NO, Michie, SA, Soetikno, RM, Resurreccion, EZ, Broome, RL, Oshima, RG & Omary, MB 1996, 'Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant', Journal of Clinical Investigation, vol. 98, no. 4, pp. 1034-1046. https://doi.org/10.1172/JCI118864

Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant. / Ku, Nam On; Michie, Sara A.; Soetikno, Roy M.; Resurreccion, Evelyn Z.; Broome, Rosemary L.; Oshima, Robert G.; Omary, M. Bishr.

In: Journal of Clinical Investigation, Vol. 98, No. 4, 15.08.1996, p. 1034-1046.

Research output: Contribution to journalArticle

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T1 - Susceptibility to hepatotoxicity in transgenic mice that express a dominant-negative human keratin 18 mutant

AU - Ku, Nam On

AU - Michie, Sara A.

AU - Soetikno, Roy M.

AU - Resurreccion, Evelyn Z.

AU - Broome, Rosemary L.

AU - Oshima, Robert G.

AU - Omary, M. Bishr

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