Characterization of nuclear receptor-mediated murine hepatocarcinogenesis of the herbicide pronamide and its human relevance.
The key events responsible for mouse liver tumors induced by a pesticide (viz., pronamide) were investigated in a series of studies employing molecular, biochemical, cellular, and apical endpoints. Based on these studies, it was demonstrated that the liver tumors were mediated by a mode of action (MoA) involving nuclear receptors (NRs) through the following key events: (1) CAR and PPAR-α receptor activation, (2) increased hepatocellular proliferation, eventually leading to (3) hepatocellular tumors. Specifically, gene expression analysis indicated robust, simultaneous coactivation of the CAR and PPAR-α NRs, as indicated by the induction of hepatic Cyp2b10 and Cyp4a10 transcripts, in response to dietary administration of pronamide to mice. The presence of hepatocellular hypertrophy and peroxisome proliferation was indicative of the activation of these two NRs at carcinogenic dose levels. Demonstrated induction of Cyp2b10 gene and protein, however, was not accompanied by enhancement of the corresponding enzyme activity (7-pentoxyresorufin-O-dealkylase (PROD)), suggesting that pronamide administration resulted in mechanism-based (suicide) inhibition of the enzyme in vivo. This was confirmed with an in vitro assay for suicide inhibition, where pronamide and/or its metabolites irreversibly inhibited Cyp2b10-mediated PROD activity. Analysis of hepatocellular proliferation via BrdU incorporation indicated a clear dose- and duration-related induction of S-phase DNA synthesis only in animals treated at and above the carcinogenic dose level. The available MoA data were evaluated for weight-of-evidence based upon the Bradford Hill criteria, followed by a human relevance framework. The conclusion from this evaluation is that pronamide-induced mouse liver tumors occur via an NR-mediated MoA involving CAR and PPAR-α activation and this MoA is not relevant to humans based on qualitative/quantitative differences between mice and humans.
['LeBaron|Matthew J|MJ|', 'Rasoulpour|Reza J|RJ|', 'Gollapudi|B Bhaskar|BB|', 'Sura|Radhakrishna|R|', 'Kan|H Lynn|HL|', 'Schisler|Melissa R|MR|', 'Pottenger|Lynn H|LH|', 'Papineni|Sabitha|S|', 'Eisenbrandt|David L|DL|']
D000818:Animals D001189:Aryl Hydrocarbon Hydroxylases D001549:Benzamides D049109:Cell Proliferation D000090702:Constitutive Androstane Receptor D003577:Cytochrome P-450 Enzyme System D000072467:Cytochrome P450 Family 2 D004305:Dose-Response Relationship, Drug D005260:Female D015870:Gene Expression D006540:Herbicides D006801:Humans D008099:Liver D008114:Liver Neoplasms, Experimental D008297:Male D008815:Mice, Inbred Strains D047493:PPAR alpha D000077297:Pregnane X Receptor D018160:Receptors, Cytoplasmic and Nuclear D011987:Receptors, Steroid D013045:Species Specificity D013250:Steroid Hydroxylases D013997:Time Factors
pesticide mode of action MoA CAR PPAR-α hepatocellular proliferation HRF constitutive androstane receptor peroxisome proliferator-activated receptor alpha plant protection product