Comparisons of protein changes in human and rodent hepatocytes induced by the rat‐specific carcinogen, methapyrilene

Abstract

There is a growing concern that the rodent bioassay may not always serve as an appropriate model to assess the carcinogenic risk for humans exposed to certain compounds. Mechanistic research that examines the effects of a compound in rodent and man could help in the interpretation of bioassay results. This paper reports a novel use of two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) technology to assess similarities and differences in the response of rodents and humans to the rat-specific hepatocarcinogen, methapyrilene (MP). A sequential examination of rodent and human hepatic proteins was conducted following in vivo exposure of rats and mice and in vitro exposure of rat, mouse, and human hepatocytes to MP. Results showed that covalent modifications observed in rats and mice in vivo were duplicated both qualitatively and quantitatively in the corresponding in vitro systems and that these modifications correlated with carcinogenic susceptibility. Covalent modifications in human hepatocytes were minimal despite exposure to concentrations of MP that were 6-fold higher than those used in rodent hepatocytes. These studies suggest that in the case of MP the rat is not the most appropriate model for assessing the human situation. Furthermore, these data show that in vitro-in vivo comparisons based on 2-D PAGE may provide adjunctive information for extrapolating rodent toxicity/bioassay results to human risk assessment.

Proteomics: Applications and opportunities in preclinical drug development

“…The protein modifications were absent following treatment with the nontumorigenic MPY analog pyrilamine [62]. Rodent hepatocytes showed modifications paralleling those observed in vivio, while human hepatocytes showed no statistically significally effect [63], a finding consistent with human epidemiological data suggesting a lack of tumors in man.…”

Systems Toxicology: Integrated Genomic, Proteomic and Metabonomic Analysis of Methapyrilene Induced Hepatotoxicity in the Rat

“…Mechanism of Methapyrilene Toxicity. Previous studies have suggested that a metabolite of methapyrilene covalently binds almost exclusively to mitochondrial protein 11,22 and that toxicity results in dislocation of the mitochondrial membranes. 20 In this present study, two mitochondrial proteins (pyruvate carboxylase and carbamoyl phosphate synthase) underwent modification to negatively charged species.…”

Separation of aromatic acids by wide‐bore electrophoresis with nanoparticles prepared by electrospray as pseudostationary phase

“…Additionally, as a result of the rapid development in genomic and proteomic science, CE has attracted increased attention due to its merits of rapid separation, high efficiency, low sample consumption, on-line detection and easy automation. Recently, there has been greater emphasis placed on using multidimensional separation approaches for enhancing abilities to identify, characterize and quantify individual components in complicated matrices [12][13][14][15]. The multidimensional separation approach requires that each preceding step in separation transfers sufficient samples for next procedure.…”