Liver hypertrophy

a review of adaptive (adverse and non-adverse) changes-conclusions from the 3rd International ESTP Expert Workshop

A. P. Hall, C. R. Elcombe, J. R. Foster, T. Harada, W. Kaufmann, A. Knippel, K. Kuettler, D. E. Malarkey, R. R. Maronpot, A. Nishikawa, T. Nolte, A. Schulte, V. Strauss, M. J. York

    Research output: Contribution to journalArticle

    136 Citations (Scopus)

    Abstract

    Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPAR alpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

    Original languageEnglish
    Pages (from-to)971-994
    Number of pages24
    JournalToxicologic Pathology
    Volume40
    Issue number7
    DOIs
    Publication statusPublished - 2012

    Keywords

    • hypertrophy
    • PXR
    • weight
    • clinical pathology
    • GAMMA-GLUTAMYL-TRANSPEPTIDASE
    • CONSTITUTIVE-ANDROSTANE RECEPTOR
    • fasting
    • PEROXISOME PROLIFERATOR WY-14,643
    • non-adverse
    • PPAR alpha
    • SPRAGUE-DAWLEY RATS
    • adverse
    • MICROSOMAL-ENZYME INDUCTION
    • DRUG-METABOLIZING-ENZYMES
    • ANDROGEN CYPROTERONE-ACETATE
    • ALKALINE-PHOSPHATASE ACTIVITY
    • ARYL-HYDROCARBON RECEPTOR
    • omics
    • PREGNANE-X-RECEPTOR
    • AhR
    • liver
    • CAR

    Cite this

    Hall, A. P. ; Elcombe, C. R. ; Foster, J. R. ; Harada, T. ; Kaufmann, W. ; Knippel, A. ; Kuettler, K. ; Malarkey, D. E. ; Maronpot, R. R. ; Nishikawa, A. ; Nolte, T. ; Schulte, A. ; Strauss, V. ; York, M. J. / Liver hypertrophy : a review of adaptive (adverse and non-adverse) changes-conclusions from the 3rd International ESTP Expert Workshop. In: Toxicologic Pathology. 2012 ; Vol. 40, No. 7. pp. 971-994.
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    abstract = "Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPAR alpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.",
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    author = "Hall, {A. P.} and Elcombe, {C. R.} and Foster, {J. R.} and T. Harada and W. Kaufmann and A. Knippel and K. Kuettler and Malarkey, {D. E.} and Maronpot, {R. R.} and A. Nishikawa and T. Nolte and A. Schulte and V. Strauss and York, {M. J.}",
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    Hall, AP, Elcombe, CR, Foster, JR, Harada, T, Kaufmann, W, Knippel, A, Kuettler, K, Malarkey, DE, Maronpot, RR, Nishikawa, A, Nolte, T, Schulte, A, Strauss, V & York, MJ 2012, 'Liver hypertrophy: a review of adaptive (adverse and non-adverse) changes-conclusions from the 3rd International ESTP Expert Workshop', Toxicologic Pathology, vol. 40, no. 7, pp. 971-994. https://doi.org/10.1177/0192623312448935

    Liver hypertrophy : a review of adaptive (adverse and non-adverse) changes-conclusions from the 3rd International ESTP Expert Workshop. / Hall, A. P.; Elcombe, C. R.; Foster, J. R.; Harada, T.; Kaufmann, W.; Knippel, A.; Kuettler, K.; Malarkey, D. E.; Maronpot, R. R.; Nishikawa, A.; Nolte, T.; Schulte, A.; Strauss, V.; York, M. J.

    In: Toxicologic Pathology, Vol. 40, No. 7, 2012, p. 971-994.

    Research output: Contribution to journalArticle

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    T1 - Liver hypertrophy

    T2 - a review of adaptive (adverse and non-adverse) changes-conclusions from the 3rd International ESTP Expert Workshop

    AU - Hall, A. P.

    AU - Elcombe, C. R.

    AU - Foster, J. R.

    AU - Harada, T.

    AU - Kaufmann, W.

    AU - Knippel, A.

    AU - Kuettler, K.

    AU - Malarkey, D. E.

    AU - Maronpot, R. R.

    AU - Nishikawa, A.

    AU - Nolte, T.

    AU - Schulte, A.

    AU - Strauss, V.

    AU - York, M. J.

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    N2 - Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPAR alpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

    AB - Preclinical toxicity studies have demonstrated that exposure of laboratory animals to liver enzyme inducers during preclinical safety assessment results in a signature of toxicological changes characterized by an increase in liver weight, hepatocellular hypertrophy, cell proliferation, and, frequently in long-term (life-time) studies, hepatocarcinogenesis. Recent advances over the last decade have revealed that for many xenobiotics, these changes may be induced through a common mechanism of action involving activation of the nuclear hormone receptors CAR, PXR, or PPAR alpha. The generation of genetically engineered mice that express altered versions of these nuclear hormone receptors, together with other avenues of investigation, have now demonstrated that sensitivity to many of these effects is rodent-specific. These data are consistent with the available epidemiological and empirical human evidence and lend support to the scientific opinion that these changes have little relevance to man. The ESTP therefore convened an international panel of experts to debate the evidence in order to more clearly define for toxicologic pathologists what is considered adverse in the context of hepatocellular hypertrophy. The results of this workshop concluded that hepatomegaly as a consequence of hepatocellular hypertrophy without histologic or clinical pathology alterations indicative of liver toxicity was considered an adaptive and a non-adverse reaction. This conclusion should normally be reached by an integrative weight of evidence approach.

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    KW - PXR

    KW - weight

    KW - clinical pathology

    KW - GAMMA-GLUTAMYL-TRANSPEPTIDASE

    KW - CONSTITUTIVE-ANDROSTANE RECEPTOR

    KW - fasting

    KW - PEROXISOME PROLIFERATOR WY-14,643

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    KW - PPAR alpha

    KW - SPRAGUE-DAWLEY RATS

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    KW - DRUG-METABOLIZING-ENZYMES

    KW - ANDROGEN CYPROTERONE-ACETATE

    KW - ALKALINE-PHOSPHATASE ACTIVITY

    KW - ARYL-HYDROCARBON RECEPTOR

    KW - omics

    KW - PREGNANE-X-RECEPTOR

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    KW - liver

    KW - CAR

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