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Inhibition of Colon Carcinogenesis*
Published in Herman Autrup, Gary M. Williams, Experimental Colon Carcinogenesis, 2019
Studies with inhibitors have increased our knowledge of the activation sequence for DMH as well as the mechanism and loci of inhibitor actions. Important contributions have been made by integrating the results of several studies on sulfur-containing compounds found to inhibit colon carcinogenesis. Disulfiram (tetraethylthiuram, Antabuse) and sodium diethyldithiocarbamate (NaDDC), when added to the diet of female CF1 mice, inhibit DMH-induced large bowel neoplasia.64,65 Two pesticides with structural similarities to disulfiram, ethylene bis(dithiocarbamato)manganese (Maneb) and bis(ethylxanthogen)(BEX), produce comparable inhibition of DMH.65 A third pesticide, chlorpropham, lacks the carbon disulfide moiety common to the above four compounds and exhibits no inhibitory effect against DMH. In a comparative study disulfiram also inhibited azoxymethane carcinogenicity, but the inhibition was less than that seen with DMH.65 All of the active inhibitors have in common the thiono sulfur group. In separate investigations disulfiram was found to be metabolized to DDC then to carbon disulfide.66,67 Inhibition of DMH carcinogenesis in male F344 rats has been reported with dietary disulfiram, NaDCC, BEX, and also with carbon disulfide.68,69 These studies support the hypothesis that the metabolism of the thiono sulfur compounds to carbon disulfide is essential to their potential to inhibit DMH-induced carcinogenesis. Other important observations have helped to elucidate the metabolic activation of DMH and sites of inhibition in the pathway. In F344 rats AOM-14C is rapidly metabolized to 14CO2.68 Pretreatment of rats with disulfiram or carbon disulfide inhibited exhaled 14CO2, decreased urinary MAM, and increased the amount of unmetabolized AOM in the exhaled air and in urine. Thus, disulfiram and carbon disulfide appear to inhibit the metabolism of AOM.
Differential interactions of carbamate pesticides with drug transporters
Published in Xenobiotica, 2020
Nelly Guéniche, Arnaud Bruyere, Mélanie Ringeval, Elodie Jouan, Antoine Huguet, Ludovic Le Hégarat, Olivier Fardel
Aminocarb, carbofuran and propamocarb, used at 100 µM, did not inhibit uptake of the reference substrates DCF and 8-FcA in HEK-OATP1B1 and HEK-OATP1B3 cells (Figure 3). Aminocarb and propamocarb also failed to modify E3S accumulation in HEK-OATP2B1 cells, whereas carbofuran slightly enhanced it (Figure 3). Chlorpropham did not alter accumulation of 8-FcA in HEK-OATP1B3 cells. By contrast, it diminished accumulation of DCF in HEK-OATP1B1 cells and that of E3S in HEK-OATP2B1 cells (Figure 3); such reductions of transporter activities were however rather modest, i.e. 100 µM chlorpropham decreased OATP1B1 and OATP2B1 activities by 37.2% and 24.9%, respectively, thus indicating that IC50 values are higher than 100 µM.