A human relevance investigation of PPARα-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats. 2018

Christian Strupp, and Werner H Bomann, and François Spézia, and Frédéric Gervais, and Roy Forster, and Lysiane Richert, and Pramila Singh
ADAMA Deutschland GmbH, Edmund-Rumpler-Str. 6, 51149 Cologne, Germany. Electronic address: chr.strupp@web.de.

Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor α (PPARα) has been postulated based on existing data. Experience with PPARα-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARα activation in wildtype (WT) compared to PPARα-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose-dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl-CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARα-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans.

UI MeSH Term Description Entries
D008099 Liver A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances. Livers
D008113 Liver Neoplasms Tumors or cancer of the LIVER. Cancer of Liver,Hepatic Cancer,Liver Cancer,Cancer of the Liver,Cancer, Hepatocellular,Hepatic Neoplasms,Hepatocellular Cancer,Neoplasms, Hepatic,Neoplasms, Liver,Cancer, Hepatic,Cancer, Liver,Cancers, Hepatic,Cancers, Hepatocellular,Cancers, Liver,Hepatic Cancers,Hepatic Neoplasm,Hepatocellular Cancers,Liver Cancers,Liver Neoplasm,Neoplasm, Hepatic,Neoplasm, Liver
D008297 Male Males
D009929 Organ Size The measurement of an organ in volume, mass, or heaviness. Organ Volume,Organ Weight,Size, Organ,Weight, Organ
D011422 Propionates Derivatives of propionic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the carboxyethane structure. Propanoate,Propanoic Acid,Propionate,Propanoates,Propanoic Acid Derivatives,Propanoic Acids,Propionic Acid Derivatives,Propionic Acids,Acid, Propanoic,Acids, Propanoic,Acids, Propionic,Derivatives, Propanoic Acid,Derivatives, Propionic Acid
D003577 Cytochrome P-450 Enzyme System A superfamily of hundreds of closely related HEMEPROTEINS found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (MIXED FUNCTION OXYGENASES). In animals, these P-450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (BIOTRANSFORMATION). They are classified, according to their sequence similarities rather than functions, into CYP gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the CYP1, CYP2, and CYP3 gene families are responsible for most drug metabolism. Cytochrome P-450,Cytochrome P-450 Enzyme,Cytochrome P-450-Dependent Monooxygenase,P-450 Enzyme,P450 Enzyme,CYP450 Family,CYP450 Superfamily,Cytochrome P-450 Enzymes,Cytochrome P-450 Families,Cytochrome P-450 Monooxygenase,Cytochrome P-450 Oxygenase,Cytochrome P-450 Superfamily,Cytochrome P450,Cytochrome P450 Superfamily,Cytochrome p450 Families,P-450 Enzymes,P450 Enzymes,Cytochrome P 450,Cytochrome P 450 Dependent Monooxygenase,Cytochrome P 450 Enzyme,Cytochrome P 450 Enzyme System,Cytochrome P 450 Enzymes,Cytochrome P 450 Families,Cytochrome P 450 Monooxygenase,Cytochrome P 450 Oxygenase,Cytochrome P 450 Superfamily,Enzyme, Cytochrome P-450,Enzyme, P-450,Enzyme, P450,Enzymes, Cytochrome P-450,Enzymes, P-450,Enzymes, P450,Monooxygenase, Cytochrome P-450,Monooxygenase, Cytochrome P-450-Dependent,P 450 Enzyme,P 450 Enzymes,P-450 Enzyme, Cytochrome,P-450 Enzymes, Cytochrome,Superfamily, CYP450,Superfamily, Cytochrome P-450,Superfamily, Cytochrome P450
D004032 Diet Regular course of eating and drinking adopted by a person or animal. Diets
D005978 Glutathione A tripeptide with many roles in cells. It conjugates to drugs to make them more soluble for excretion, is a cofactor for some enzymes, is involved in protein disulfide bond rearrangement and reduces peroxides. Reduced Glutathione,gamma-L-Glu-L-Cys-Gly,gamma-L-Glutamyl-L-Cysteinylglycine,Glutathione, Reduced,gamma L Glu L Cys Gly,gamma L Glutamyl L Cysteinylglycine
D005979 Glutathione Peroxidase An enzyme catalyzing the oxidation of 2 moles of GLUTATHIONE in the presence of HYDROGEN PEROXIDE to yield oxidized glutathione and water. Cytosolic Glutathione Peroxidase,Glutathione Lipoperoxidase,Selenoglutathione Peroxidase,Glutathione Peroxidase, Cytosolic,Lipoperoxidase, Glutathione,Peroxidase, Glutathione,Peroxidase, Selenoglutathione
D006540 Herbicides Pesticides used to destroy unwanted vegetation, especially various types of weeds, grasses (POACEAE), and woody plants. Some plants develop HERBICIDE RESISTANCE. Algaecide,Algicide,Herbicide,Algaecides,Algicides

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