Is the question of phenobarbital as potential liver cancer risk factor for humans really resolved?

Braeuning, Albert; Schwarz, Michael

doi:10.1007/s00204-016-1712-0

Cited by 22 publications

(20 citation statements)

References 7 publications

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“…Therefore, some researchers have suggested that the human relevance of the tumorigenicity of PB through CAR activation remains the subject of an ongoing debate (Braeuning, 2014;Braeuning and Schwarz, 2016;Braeuning et al, 2015;Marx-Stoelting et al, 2017;Groll et al, 2016). We recognize that the human receptors of hCAR/hPXR mouse model are operational in a mouse hepatocyte environment.…”

Section: Human Applicability Of the Proposed Mode Of Actionmentioning

confidence: 99%

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: Human Applicability Of the Proposed Mode Of Actionmentioning

confidence: 99%

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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“…62 Schwartz and Braeuning's group indicated that the human relevance of the tumorigenicity of PB through CAR activation remains the subject of an ongoing debate. [63][64][65][66][67] The genetically humanized model may be a useful model for human prediction in some cases, 68 but we should also recognize its disadvantages. A comparison between genetically humanized and chimeric humanized mouse liver models was discussed from the perspective of studies on drug metabolism and toxicity.…”

Section: Further Evaluation Of Molecular Key Events Of Car-mediated Moamentioning

confidence: 99%

Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action

Yamada

2018

Toxicology Research

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“…Studies of hepatotoxicity often rely on the correct interpretation of histology (Schenk et al, 2017[ 18 ]; Reif et al, 2017[ 17 ]; Ghallab et al, 2016[ 8 ]; Vartak et al, 2016[ 20 ]; Nussler et al, 2014[ 16 ]; Drasdo et al, 2014[ 6 ]; Campos et al, 2014[ 3 ]; Braeuning and Schwarz, 2016[ 2 ]; Chen et al, 2015[ 4 ]; Crespo Yanguas et al, 2016[ 5 ]). Also liver physiology and regeneration depend on optimal zonation (Jansen et al, 2017[ 12 ]; Hoehme et al, 2010[ 11 ]; Bartl et al, 2015[ 1 ]; Yanguas et al, 2016[ 21 ]; Stöber, 2016[ 19 ]; Moghbel et al, 2016[ 15 ]): moreover 3D in vitro systems in toxicology aim for mimicking some of the zonated features of the liver lobule (Frey et al, 2014[ 7 ]; Kim et al, 2015[ 13 ]; Leist et al, 2017[ 14 ]).…”

Section: ⁯⁯mentioning

confidence: 99%

Highlight report: The pseudolobule in liver fibrosis

2017

EXCLI Journal; 16:Doc1321; ISSN 1611-2156

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Is the question of phenobarbital as potential liver cancer risk factor for humans really resolved?

Cited by 22 publications

References 7 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

Case examples of an evaluation of the human relevance of the pyrethroids/pyrethrins-induced liver tumours in rodents based on the mode of action

Highlight report: The pseudolobule in liver fibrosis

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