Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes

Hirose, Y; Nagahori, Hirohisa; Yamada, Tomoya; Deguchi, Yoshihito; Tomigahara, Yoshitaka; Nishioka, Kazuhiko; Uwagawa, Satoshi; Kawamura, Satoshi; Isobe, Naohiko; Lake, Brian G.; Okuno, Yasuyoshi

doi:10.1016/j.tox.2009.01.007

Cited by 47 publications

(66 citation statements)

References 24 publications

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“…We have provided some experimental data showing a key species difference; those were that while PB stimulates replicative DNA synthesis in rodent hepatocytes, such proliferative effects are not observed in cultured human hepatocytes (Yamada et al, 2015;Hirose et al, 2009) nor in human hepatocytes of chimeric mice (Yamada et al, 2014). The lack of this key event in humans strongly supports the previous conclusion that the rodent carcinogenicity by CAR activators such as PB is not relevant to humans based on experimental and epidemiology data .…”

Section: Epsilon-momfluorothrinsupporting

confidence: 66%

“…Rat hepatocytes were isolated by a two-step perfusion procedure from HarlanRccHanTM:WIST male rats aged 10 weeks (purchased from Japan Laboratory Animals, Inc., Hanno Breeding Center, Saitama, Japan) (Hirose et al, 2009;Yamada et al, 2015). Viability (range 80-92%) was determined by trypan blue exclusion.…”

Section: Cultured Hepatocyte Study Hepatocytesmentioning

confidence: 99%

“…For assays of replicative DNA synthesis, rat and human hepatocytes were plated at a density of 1.0 x 10 4 and 3.5 x 10 4 cells/well per 100 μL of medium containing the above additions, respectively, in 96-well plates. All tissue culture plates were coated with collagen I (AsahiTechnoGlass, Shizuoka, Japan) and the hepatocytes were cultured at 37ºC in a humidified incubator under an atmosphere of 95% air/5% carbon dioxide (Yamada et al, 2015;Hirose et al, 2009).…”

Section: Cultured Hepatocyte Study Hepatocytesmentioning

confidence: 99%

“…Thus, momfluorothrin (1-1,000 μM) and Z-CMCA (5-1,000 μM) were used in this experiment. For NaPB and hHGF, concentrations indicating expected response were used based on previous studies (Hirose et al, 2009;Yamada et al, 2015).…”

Section: Chemical Treatmentmentioning

confidence: 99%

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Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

et al. 2017

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-High dietary levels of the non-genotoxic synthetic pyrethroid momfluorothrin increased the incidence of hepatocellular tumors in male and female Wistar rats. Mechanistic studies have demonstrated that the mode of action (MOA) for momfluorothrin-induced hepatocellular tumors is constitutive androstane receptor (CAR)-mediated. In the present study, to evaluate the potential human carcinogenic risk of momfluorothrin, the effects of momfluorothrin (1-1,000 μM) and a major metabolite Z-CM-CA (5-1,000 μM) on hepatocyte replicative DNA synthesis and CYP2B mRNA expression were examined in cultured rat and human hepatocyte preparations. The effect of sodium phenobarbital (NaPB), a prototypic rodent hepatocarcinogen with a CAR-mediated MOA, was also investigated. Human hepatocyte growth factor (hHGF) produced a concentration-dependent increase in replicative DNA synthesis in rat and human hepatocytes. However, while NaPB and momfluorothrin increased replicative DNA synthesis in rat hepatocytes, NaPB, momfluorothrin and Z-CMCA did not increase replicative DNA synthesis in human hepatocytes. NaPB, momfluorothrin and Z-CMCA increased CYP2B1/2 mRNA levels in rat hepatocytes. NaPB and momfluorothrin also increased CYP2B6 mRNA levels in human hepatocytes. Overall, while momfluorothrin and NaPB activated CAR in cultured human hepatocytes, neither chemical increased replicative DNA synthesis. Furthermore, to confirm whether the findings observed in vitro were also observed in vivo, a humanized chimeric mouse study was conducted. Replicative DNA synthesis was not increased in human hepatocytes of chimeric mice treated with momfluorothrin or its close structural analogue metofluthrin. As human hepatocytes are refractory to the mitogenic effects of momfluorothrin, in contrast to rat hepatocytes, the data support the hypothesis that the MOA for momfluorothrin-induced rat liver tumor formation is not relevant for humans.

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Section: Epsilon-momfluorothrinsupporting

confidence: 66%

Section: Cultured Hepatocyte Study Hepatocytesmentioning

confidence: 99%

Section: Cultured Hepatocyte Study Hepatocytesmentioning

confidence: 99%

Section: Chemical Treatmentmentioning

confidence: 99%

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Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

et al. 2017

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“…This observation is based on the resistance of cultured human hepatocytes to induction of replicative DNA synthesis (Hirose et al 2009;Lake 2009;Parzefall et al 1991) as well as similar observations in huPXR/huCAR receptor humanized mice.…”

Section: Epidemiology and Risk To Manmentioning

confidence: 83%

Liver Hypertrophy

Elcombe²,

et al. 2012

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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 PPARa. 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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Perfluoroctansulfonsäure und ihre Salze [MAK Value Documentation in German language, 2011]

2012

The MAK‐Collection for Occupational Health and Safety

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Veröffentlicht in der Reihe Gesundheitsschädliche Arbeitsstoffe , 51. Lieferung, Ausgabe 2011 Der Artikel enthält folgende Kapitel: Allgemeiner Wirkungscharakter Toxikokinetik und Metabolismus Aufnahme, Verteilung, Ausscheidung Metabolismus Erfahrungen beim Menschen Tierexperimentelle Befunde und In‐vitro‐Untersuchungen Akute Toxizität Subakute, subchronische und chronische Toxizität Wirkung auf Haut und Schleimhäute Allergene Wirkung Reproduktionstoxizität Genotoxizität Kanzerogenität Bewertung

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Comparison of the effects of the synthetic pyrethroid Metofluthrin and phenobarbital on CYP2B form induction and replicative DNA synthesis in cultured rat and human hepatocytes

Cited by 47 publications

References 24 publications

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

Liver Hypertrophy

Perfluoroctansulfonsäure und ihre Salze [MAK Value Documentation in German language, 2011]

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