Metabolism of triflumuron in the human liver: Contribution of cytochrome P450 isoforms and esterases.

Abstract Triflumuron (TFM) is a benzoylurea insecticide commonly used in Tunisian agriculture and around the world to control crop pests and flies as a promising alternative to conventional insecticides for its arthropod specificity and low toxicity. From the evidence available in animal models, it can be expected that the metabolism of TFM is catalyzed by cytochrome P450 (CYP) and esterases. However, no data are available on human metabolism of TFM with regards to phase I metabolism and CYP isoform specificity. Hence, this manuscript describes experimental investigations to underpin in vitro phase I TFM metabolism in human samples for the first time. TFM biotransformation by recombinant human CYPs was characterized, then human liver microsomes (HLM) and chemical specific inhibitors have been used to identify the relative contribution of CYPs and esterases. Our results showed that all CYP isoforms were able to metabolize TFM with different affinity and efficiency. The relative contribution based both on the kinetic parameters and the CYP hepatic content was 3A4 > >2C9 > 2C8 > 2A6 > 1A2 > 2B6 > 2D6 > 2C19 > 2C18 > 1A1 at low TFM concentration, whilst at high TFM concentration it was 1A2 > >2C9 = 3A4 = 2A6 > 2C19 > 2B6 = 2C8 > 2D6 > 1A1 > 2C18. Experiments with HLMs confirmed the involvement of the most relevant CYPs in the presence of specific chemical inhibitors with a catalytic efficiency (Cliapp) lower by an order of magnitude compared with recombinant enzymes. Esterases were also relevant to the overall TFM kinetics and metabolism, with catalytic efficiency higher than that of CYPs. It is foreseen that such isoform-specific information in humans will further support in silico models for the refinement of the human risk assessment of single pesticides or mixtures

The implication of ROS production on triflumuron-induced oxidative stress and genotoxicity in human colon carcinoma (HCT-116) cells

The aim of this study is to evaluate the cytotoxic and the genotoxic effects of triflumuron (TFM) on human colon carcinoma cells (HCT-116). Indeed, TFM is used to protect vegetables, fruits, and domestic animals against a large spectrum of parasites causing animal and human disorders. However, studies revealing its toxicity and its mode of action in mammalian systems remain very limited. We monitored our work with the cytotoxicity assay starting with the cell viability test, the ROS generation, the malondialdehyde (MDA) production, the DNA fragmentation, and the measurement of some antioxidant enzymes activities such as catalase, superoxide dismutase, and the glutathione S-transferase. Also, we measured the mitochondrial transmembrane potential. We showed that TFM induced a dose-dependent cell death. This decrease in cell viability was accompanied by a significant reduction in the mitochondrial membrane potential. We also have shown that TFM induced oxidative stress as revealed by the generation of reactive oxygen species, the increase of the MDA levels, and the activation of the antioxidant enzymes. Moreover, our results indicated that TFM induced DNA damage in HCT-116 cells as monitored by the comet assay. We demonstrate, for the first time, the cytotoxic and the genotoxic potentials of TFM on human cultured cells

Partial characterization of the edible Spinacia oleracea polysaccharides: Cytoprotective and antioxidant potentials against Cd induced toxicity in HCT116 and HEK293 cells

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